Yichuan Liu, Hui-Qi Qu, Xiao Chang, Frank D Mentch, Haijun Qiu, Kenny Nguyen, Kayleigh Ostberg, Tiancheng Wang, Joseph Glessner, Hakon Hakonarson
<p>Childhood solid tumors represent a significant public health challenge worldwide, with approximately 15,000 new cases annually in the United States and an estimated 300,000 globally. Down syndrome (DS), a genetic disorder characterized by an extra full or partial copy of chromosome 21, results in distinctive developmental and physical features. Notably, individuals with DS exhibit a remarkable resilience against solid tumors compared to the general population, with an overall standardized incidence ratio (SIR) of 0.45, despite their increased susceptibility to hematologic malignancies [<span>1</span>]. This paradoxical observation has spurred extensive research aimed at uncovering the biological underpinnings of this natural resistance to solid cancers. Current theories suggest that the overexpression of specific genes on chromosome 21 may confer protective benefits (e.g. <i>RCAN1</i> contributes to antiangiogenic effects), and alterations in immune system function may enhance apoptosis and DNA repair pathways in individuals with trisomy 21 DS [<span>2</span>]. The well-established epigenetic effects of trisomy 21, which influence the entire genome, are another potential contributor to the reduced risk of solid tumors [<span>3</span>]. Nonetheless, these hypotheses face significant challenges, such as the potential oversimplification of complex genetic interactions and the lack of comprehensive genome-wide analyses. This study seeks to critically evaluate the correlations between genomic variants and cancer clinical phenotypes in patients with DS, and proposes directions for future research into the genetic and molecular mechanisms that confer cancer resistance in DS, potentially transforming our understanding and treatment of pediatric cancers.</p><p>We conducted an innovative unbiased data-driven analysis in 2,452 whole-genome sequencing (WGS) samples with both DS individuals (<i>n</i> = 635) and pediatric oncology cases (<i>n</i> = 280) within the Gabriella Miller Kids First program project (https://kidsfirstdrc.org/) housed at the Children's Hospital of Philadelphia (Supplementary Figure S1). Additionally, 284 RNA sequencing samples from human peripheral blood mononuclear cells (PBMCs), a subset of WGS samples, were also analyzed, offering unprecedented insights into the complex interplay of genetic and immunological factors influencing cancer resistance.</p><p>The importance of each variant was calculated using deep learning algorithms, and their corresponding weights to DS cancer were generated based on linear algebra models as described in the Supplementary Materials and Methods. There were 2,523 unique cancer protective variants identified based on deep learning algorithms combined with linear algebra models in exonic, intronic, non-coding RNA and 5’untranslated region (5’UTR) regions. The prevalence for cancer protective variants in the DS cancer group (89.2%) is significantly higher compared to non-DS cancer individuals (58.1%) (<i>P
{"title":"Deciphering protective genomic factors of tumor development in pediatric Down syndrome via deep learning approach to whole genome and RNA sequencing","authors":"Yichuan Liu, Hui-Qi Qu, Xiao Chang, Frank D Mentch, Haijun Qiu, Kenny Nguyen, Kayleigh Ostberg, Tiancheng Wang, Joseph Glessner, Hakon Hakonarson","doi":"10.1002/cac2.12612","DOIUrl":"10.1002/cac2.12612","url":null,"abstract":"<p>Childhood solid tumors represent a significant public health challenge worldwide, with approximately 15,000 new cases annually in the United States and an estimated 300,000 globally. Down syndrome (DS), a genetic disorder characterized by an extra full or partial copy of chromosome 21, results in distinctive developmental and physical features. Notably, individuals with DS exhibit a remarkable resilience against solid tumors compared to the general population, with an overall standardized incidence ratio (SIR) of 0.45, despite their increased susceptibility to hematologic malignancies [<span>1</span>]. This paradoxical observation has spurred extensive research aimed at uncovering the biological underpinnings of this natural resistance to solid cancers. Current theories suggest that the overexpression of specific genes on chromosome 21 may confer protective benefits (e.g. <i>RCAN1</i> contributes to antiangiogenic effects), and alterations in immune system function may enhance apoptosis and DNA repair pathways in individuals with trisomy 21 DS [<span>2</span>]. The well-established epigenetic effects of trisomy 21, which influence the entire genome, are another potential contributor to the reduced risk of solid tumors [<span>3</span>]. Nonetheless, these hypotheses face significant challenges, such as the potential oversimplification of complex genetic interactions and the lack of comprehensive genome-wide analyses. This study seeks to critically evaluate the correlations between genomic variants and cancer clinical phenotypes in patients with DS, and proposes directions for future research into the genetic and molecular mechanisms that confer cancer resistance in DS, potentially transforming our understanding and treatment of pediatric cancers.</p><p>We conducted an innovative unbiased data-driven analysis in 2,452 whole-genome sequencing (WGS) samples with both DS individuals (<i>n</i> = 635) and pediatric oncology cases (<i>n</i> = 280) within the Gabriella Miller Kids First program project (https://kidsfirstdrc.org/) housed at the Children's Hospital of Philadelphia (Supplementary Figure S1). Additionally, 284 RNA sequencing samples from human peripheral blood mononuclear cells (PBMCs), a subset of WGS samples, were also analyzed, offering unprecedented insights into the complex interplay of genetic and immunological factors influencing cancer resistance.</p><p>The importance of each variant was calculated using deep learning algorithms, and their corresponding weights to DS cancer were generated based on linear algebra models as described in the Supplementary Materials and Methods. There were 2,523 unique cancer protective variants identified based on deep learning algorithms combined with linear algebra models in exonic, intronic, non-coding RNA and 5’untranslated region (5’UTR) regions. The prevalence for cancer protective variants in the DS cancer group (89.2%) is significantly higher compared to non-DS cancer individuals (58.1%) (<i>P","PeriodicalId":9495,"journal":{"name":"Cancer Communications","volume":"44 11","pages":"1374-1378"},"PeriodicalIF":20.1,"publicationDate":"2024-10-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/cac2.12612","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142458708","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Xue Xiao, Wei Wang, Peng Bai, Ying Chen, Zhengwen Qin, Tong Cheng, Xing Li, John P. Pineda, Panying Shi, Xiaonan Wang, Jianhong Wang, Lian Xu, Xuemei Gao, Huixian Zheng, Lulu Yang, Wenyi Lin, Wenbin Huang, Rulong Shen, Changjun Yue, Huixiong Xu, Felipe Batalini, Yang Liu, Ning Zhou, Yaoyao Zhang, Hanmin Liu
<p>Cervical cancer remains a significant global public health issue due to its high incidence and mortality. Current clinical guidelines recommend screening for high-risk human papillomavirus (hrHPV)-DNA alongside a Thinprep cytologic test (TCT) before further medical evaluation [<span>1</span>]. The hrHPV-DNA test detects 14 high-risk HPV genotypes including the predominant hrHPV16/18, which can cause cervical abnormalities that may progress to cancer if untreated. TCT is paired with the hrHPV-DNA test to pathologically classify cervical specimens into categories based on increasing malignancy risks. Despite the high sensitivities, both tests have high false positive rates which lead to unnecessary colposcopy while HPV is cleared naturally in most women without progressing into lesions. To reduce overdiagnosis and overtreatment, several DNA methylation detections [<span>2, 3</span>] have been developed for triaging the malignancy risk of hrHPV-positive cervical lesions, but have yet to become clinically available. Here, we proposed an epigenetic biomarker panel based on imprinting alterations as a high-performance triage method to improve cervical cancer risk assessment accuracy in hrHPV-positive women.</p><p>Loss of imprinting (LOI), an early molecular event in carcinogenesis, is an epigenetic phenomenon when a normally silenced allele of the imprinted gene is activated and expressed [<span>4</span>]. Using the quantitative chromogenic imprinted gene in-situ hybridization (QCIGISH) to visualize and quantify imprinted genes’ transcription sites in the nuclei, early epigenetic changes through LOI have been shown as effective biomarkers for detecting multiple malignancies [<span>5</span>]. In the present study, we first screened imprinted gene candidates using resected cervical tissue samples and subsequently developed a cancer risk stratification method based on cytological specimens diagnosed by colposcopy and biopsy (Supplementary Figure S1). The diagnostic model was blindly validated in prospectively collected cytological samples by comparing the QCIGISH results with colposcopy biopsy pathology. Full study protocols are detailed in the Supplementary file.</p><p>To identify the most efficient biomarker panel for differentiating malignancy in cervical lesions, we evaluated four candidate imprinted genes based on prior research evidence and targeted literature review of female cancers: guanine nucleotide-binding protein, alpha-stimulating complex locus (<i>GNAS</i>) related to thyroid cancer, osteosarcoma, and skin cancer [<span>6</span>], small nuclear ribonucleoprotein polypeptide N (<i>SNRPN</i>) associated with seminoma, yolk sac tumor, and acute myeloid leukemia [<span>7</span>], histocompatibility minor 13 (<i>HM13</i>) linked to breast cancer [<span>8</span>], and small nuclear ribonucleoprotein 13 (<i>SNU13</i>) involved with lung cancer [<span>9</span>]. QCIGISH was applied to 79 formalin-fixed paraffin-embedded samples comprised of 30 b
{"title":"Genomic imprinting biomarkers for cervical cancer risk stratification","authors":"Xue Xiao, Wei Wang, Peng Bai, Ying Chen, Zhengwen Qin, Tong Cheng, Xing Li, John P. Pineda, Panying Shi, Xiaonan Wang, Jianhong Wang, Lian Xu, Xuemei Gao, Huixian Zheng, Lulu Yang, Wenyi Lin, Wenbin Huang, Rulong Shen, Changjun Yue, Huixiong Xu, Felipe Batalini, Yang Liu, Ning Zhou, Yaoyao Zhang, Hanmin Liu","doi":"10.1002/cac2.12617","DOIUrl":"10.1002/cac2.12617","url":null,"abstract":"<p>Cervical cancer remains a significant global public health issue due to its high incidence and mortality. Current clinical guidelines recommend screening for high-risk human papillomavirus (hrHPV)-DNA alongside a Thinprep cytologic test (TCT) before further medical evaluation [<span>1</span>]. The hrHPV-DNA test detects 14 high-risk HPV genotypes including the predominant hrHPV16/18, which can cause cervical abnormalities that may progress to cancer if untreated. TCT is paired with the hrHPV-DNA test to pathologically classify cervical specimens into categories based on increasing malignancy risks. Despite the high sensitivities, both tests have high false positive rates which lead to unnecessary colposcopy while HPV is cleared naturally in most women without progressing into lesions. To reduce overdiagnosis and overtreatment, several DNA methylation detections [<span>2, 3</span>] have been developed for triaging the malignancy risk of hrHPV-positive cervical lesions, but have yet to become clinically available. Here, we proposed an epigenetic biomarker panel based on imprinting alterations as a high-performance triage method to improve cervical cancer risk assessment accuracy in hrHPV-positive women.</p><p>Loss of imprinting (LOI), an early molecular event in carcinogenesis, is an epigenetic phenomenon when a normally silenced allele of the imprinted gene is activated and expressed [<span>4</span>]. Using the quantitative chromogenic imprinted gene in-situ hybridization (QCIGISH) to visualize and quantify imprinted genes’ transcription sites in the nuclei, early epigenetic changes through LOI have been shown as effective biomarkers for detecting multiple malignancies [<span>5</span>]. In the present study, we first screened imprinted gene candidates using resected cervical tissue samples and subsequently developed a cancer risk stratification method based on cytological specimens diagnosed by colposcopy and biopsy (Supplementary Figure S1). The diagnostic model was blindly validated in prospectively collected cytological samples by comparing the QCIGISH results with colposcopy biopsy pathology. Full study protocols are detailed in the Supplementary file.</p><p>To identify the most efficient biomarker panel for differentiating malignancy in cervical lesions, we evaluated four candidate imprinted genes based on prior research evidence and targeted literature review of female cancers: guanine nucleotide-binding protein, alpha-stimulating complex locus (<i>GNAS</i>) related to thyroid cancer, osteosarcoma, and skin cancer [<span>6</span>], small nuclear ribonucleoprotein polypeptide N (<i>SNRPN</i>) associated with seminoma, yolk sac tumor, and acute myeloid leukemia [<span>7</span>], histocompatibility minor 13 (<i>HM13</i>) linked to breast cancer [<span>8</span>], and small nuclear ribonucleoprotein 13 (<i>SNU13</i>) involved with lung cancer [<span>9</span>]. QCIGISH was applied to 79 formalin-fixed paraffin-embedded samples comprised of 30 b","PeriodicalId":9495,"journal":{"name":"Cancer Communications","volume":"44 12","pages":"1385-1390"},"PeriodicalIF":20.1,"publicationDate":"2024-10-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11666962/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142399494","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Ji Jiang, Pengfei Ye, Ningning Sun, Weihua Zhu, Mei Yang, Manman Yu, Jingjing Yu, Hui Zhang, Zijie Gao, Ningjie Zhang, Shijie Guo, Yuru Ji, Siqi Li, Cuncun Zhang, Sainan Miao, Mengqi Chai, Wenmin Liu, Yue An, Jian Hong, Wei Wei, Shihao Zhang, Huan Qiu
Background
Despite significant strides in lung cancer immunotherapy, the response rates for Kirsten rat sarcoma viral oncogene homolog (KRAS)-driven lung adenocarcinoma (LUAD) patients remain limited. Fibrinogen-like protein 1 (FGL1) is a newly identified immune checkpoint target, and the study of related resistance mechanisms is crucial for improving the treatment outcomes of LUAD patients. This study aimed to elucidate the potential mechanism by which FGL1 regulates the tumor microenvironment in KRAS-mutated cancer.
Methods
The expression levels of FGL1 and SET1 histone methyltransferase (SET1A) in lung cancer were assessed using public databases and clinical samples. Lentiviruses were constructed for transduction to overexpress or silence FGL1 in lung cancer cells and mouse models. The effects of FGL1 and Yes-associated protein (Yap) on the immunoreactivity of cytotoxic T cells in tumor tissues were evaluated using immunofluorescence staining and flow cytometry. Chromatin immunoprecipitation and dual luciferase reporter assays were used to study the SET1A-directed transcriptional program.
Results
Upregulation of FGL1 expression in KRAS-mutated cancer was inversely correlated with the infiltration of CD8+ T cells. Mechanistically, KRAS activated extracellular signal-regulated kinase 1/2 (ERK1/2), which subsequently phosphorylated SET1A and increased its stability and nuclear localization. SET1A-mediated methylation of Yap led to Yap sequestration in the nucleus, thereby promoting Yap-induced transcription of FGL1 and immune evasion in KRAS-driven LUAD. Notably, dual blockade of programmed cell death-1 (PD-1) and FGL1 further increased the therapeutic efficacy of anti-PD-1 immunotherapy in LUAD patients.
Conclusion
FGL1 could be used as a diagnostic biomarker of KRAS-mutated lung cancer, and targeting the Yap-FGL1 axis could increase the efficacy of anti-PD-1 immunotherapy.
{"title":"Yap methylation-induced FGL1 expression suppresses anti-tumor immunity and promotes tumor progression in KRAS-driven lung adenocarcinoma","authors":"Ji Jiang, Pengfei Ye, Ningning Sun, Weihua Zhu, Mei Yang, Manman Yu, Jingjing Yu, Hui Zhang, Zijie Gao, Ningjie Zhang, Shijie Guo, Yuru Ji, Siqi Li, Cuncun Zhang, Sainan Miao, Mengqi Chai, Wenmin Liu, Yue An, Jian Hong, Wei Wei, Shihao Zhang, Huan Qiu","doi":"10.1002/cac2.12609","DOIUrl":"10.1002/cac2.12609","url":null,"abstract":"<div>\u0000 \u0000 \u0000 <section>\u0000 \u0000 <h3> Background</h3>\u0000 \u0000 <p>Despite significant strides in lung cancer immunotherapy, the response rates for Kirsten rat sarcoma viral oncogene homolog (<i>KRAS</i>)-driven lung adenocarcinoma (LUAD) patients remain limited. Fibrinogen-like protein 1 (FGL1) is a newly identified immune checkpoint target, and the study of related resistance mechanisms is crucial for improving the treatment outcomes of LUAD patients. This study aimed to elucidate the potential mechanism by which FGL1 regulates the tumor microenvironment in <i>KRAS</i>-mutated cancer.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Methods</h3>\u0000 \u0000 <p>The expression levels of FGL1 and SET1 histone methyltransferase (SET1A) in lung cancer were assessed using public databases and clinical samples. Lentiviruses were constructed for transduction to overexpress or silence FGL1 in lung cancer cells and mouse models. The effects of FGL1 and Yes-associated protein (Yap) on the immunoreactivity of cytotoxic T cells in tumor tissues were evaluated using immunofluorescence staining and flow cytometry. Chromatin immunoprecipitation and dual luciferase reporter assays were used to study the SET1A-directed transcriptional program.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Results</h3>\u0000 \u0000 <p>Upregulation of FGL1 expression in <i>KRAS</i>-mutated cancer was inversely correlated with the infiltration of CD8<sup>+</sup> T cells. Mechanistically, <i>KRAS</i> activated extracellular signal-regulated kinase 1/2 (ERK1/2), which subsequently phosphorylated SET1A and increased its stability and nuclear localization. SET1A-mediated methylation of Yap led to Yap sequestration in the nucleus, thereby promoting Yap-induced transcription of FGL1 and immune evasion in <i>KRAS</i>-driven LUAD. Notably, dual blockade of programmed cell death-1 (PD-1) and FGL1 further increased the therapeutic efficacy of anti-PD-1 immunotherapy in LUAD patients.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Conclusion</h3>\u0000 \u0000 <p>FGL1 could be used as a diagnostic biomarker of <i>KRAS</i>-mutated lung cancer, and targeting the Yap-FGL1 axis could increase the efficacy of anti-PD-1 immunotherapy.</p>\u0000 </section>\u0000 </div>","PeriodicalId":9495,"journal":{"name":"Cancer Communications","volume":"44 11","pages":"1350-1373"},"PeriodicalIF":20.1,"publicationDate":"2024-09-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/cac2.12609","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142342201","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
<p>Epidemiological evidence indicates that major depressive disorder (MDD) may predispose the development and prognosis of breast cancer (BC) in females [<span>1</span>]. However, the mechanisms linking these phenotypes are not fully understood. Chronic stress, a hallmark of depression, has been underscored to affect anti-tumor immunity, tumor metabolic reprogramming, hormone synthesis in BC [<span>2, 3</span>], and increase tumor metastasis [<span>4</span>], but there is a lack of detailed cellular-level characterization of how MDD history affects the tumorigenesis of BC. This study explored the single-cell atlas of multiple tissues from BC patients with and without a history of MDD for characterizing the potential molecular alternations in their tumorigenesis (Figure 1A).</p><p>Paired primary tumor tissues (<i>n</i> = 10), adjacent normal tissues (<i>n</i> = 7), and peripheral blood samples (<i>n</i> = 10) were collected from a cohort of 10 BC patients, 5 of whom had a history of MDD (Supplementary Table S1). All BC patients had estrogen receptor (ER)-positive tumors and were further predicted as Luminal A (<i>n</i> = 9) and B subtypes (<i>n</i> = 1) (Supplementary Table S2). Further details on patient recruitment, sample handling, and single-cell data analysis are provided in Supplementary Methods. In total, we obtained 224,557 single cells and further annotated them into major cell subsets based on lineage markers and copy number variations [<span>5</span>] (Figure 1B, Supplementary Figure S1A-B). Aneuploid cells in primary tumor tissues were obtained (Supplementary Table S3) to characterize their phenotypic differences in BC patients with MDD history (BC-MDD) or not (BC-Ctrl). The Uniform Manifold Approximation and Projection (UMAP) of unintegrated aneuploid cells revealed intrinsic differences across individual patients (Supplementary Figure S1C). Downstream functional profiling analysis identified distinct immune response pathways in BC-MDD and BC-Ctrl groups and enrichment of the oxidative phosphorylation (OXPHOS) pathway in BC-Ctrl tumors (Supplementary Figure S1D-E). Cellular Gene Set Variation Analysis (GSVA) [<span>6</span>] confirmed the distinct metabolic phenotypes between BC-MDD and BC-Ctrl groups (Figure 1C). Additionally, utilizing predefined gene module (GM) signatures of BC tumor cells [<span>7</span>], we observed specific restraint of GM4 and GM6 in BC-MDD (Supplementary Figure S1F-G). GM6 encompasses various antigen presentation genes, aligning with the observed downregulation of major histocompatibility complex class I (MHC-I) class genes in BC-MDD tumor cells (Supplementary Figure S1H).</p><p>Upon re-clustering 12,371 normal epithelial cells within primary breast tumor and adjacent normal tissues from the 10 patients, we identified 9 cell clusters, including luminal hormone-responsive (LumHR), luminal secretory (LumSec), and myoepithelial cells [<span>8</span>] (Supplementary Figure S2A-B). Distribution analysis suggested
{"title":"Single-cell transcriptomic atlas reveals immune and metabolism perturbation of depression in the pathogenesis of breast cancer","authors":"Lingling Wu, Junwei Liu, Yimeng Geng, Jianwen Fang, Xingle Gao, Jianbo Lai, Minya Yao, Shaojia Lu, Weiwei Yin, Peifen Fu, Wei Chen, Shaohua Hu","doi":"10.1002/cac2.12603","DOIUrl":"10.1002/cac2.12603","url":null,"abstract":"<p>Epidemiological evidence indicates that major depressive disorder (MDD) may predispose the development and prognosis of breast cancer (BC) in females [<span>1</span>]. However, the mechanisms linking these phenotypes are not fully understood. Chronic stress, a hallmark of depression, has been underscored to affect anti-tumor immunity, tumor metabolic reprogramming, hormone synthesis in BC [<span>2, 3</span>], and increase tumor metastasis [<span>4</span>], but there is a lack of detailed cellular-level characterization of how MDD history affects the tumorigenesis of BC. This study explored the single-cell atlas of multiple tissues from BC patients with and without a history of MDD for characterizing the potential molecular alternations in their tumorigenesis (Figure 1A).</p><p>Paired primary tumor tissues (<i>n</i> = 10), adjacent normal tissues (<i>n</i> = 7), and peripheral blood samples (<i>n</i> = 10) were collected from a cohort of 10 BC patients, 5 of whom had a history of MDD (Supplementary Table S1). All BC patients had estrogen receptor (ER)-positive tumors and were further predicted as Luminal A (<i>n</i> = 9) and B subtypes (<i>n</i> = 1) (Supplementary Table S2). Further details on patient recruitment, sample handling, and single-cell data analysis are provided in Supplementary Methods. In total, we obtained 224,557 single cells and further annotated them into major cell subsets based on lineage markers and copy number variations [<span>5</span>] (Figure 1B, Supplementary Figure S1A-B). Aneuploid cells in primary tumor tissues were obtained (Supplementary Table S3) to characterize their phenotypic differences in BC patients with MDD history (BC-MDD) or not (BC-Ctrl). The Uniform Manifold Approximation and Projection (UMAP) of unintegrated aneuploid cells revealed intrinsic differences across individual patients (Supplementary Figure S1C). Downstream functional profiling analysis identified distinct immune response pathways in BC-MDD and BC-Ctrl groups and enrichment of the oxidative phosphorylation (OXPHOS) pathway in BC-Ctrl tumors (Supplementary Figure S1D-E). Cellular Gene Set Variation Analysis (GSVA) [<span>6</span>] confirmed the distinct metabolic phenotypes between BC-MDD and BC-Ctrl groups (Figure 1C). Additionally, utilizing predefined gene module (GM) signatures of BC tumor cells [<span>7</span>], we observed specific restraint of GM4 and GM6 in BC-MDD (Supplementary Figure S1F-G). GM6 encompasses various antigen presentation genes, aligning with the observed downregulation of major histocompatibility complex class I (MHC-I) class genes in BC-MDD tumor cells (Supplementary Figure S1H).</p><p>Upon re-clustering 12,371 normal epithelial cells within primary breast tumor and adjacent normal tissues from the 10 patients, we identified 9 cell clusters, including luminal hormone-responsive (LumHR), luminal secretory (LumSec), and myoepithelial cells [<span>8</span>] (Supplementary Figure S2A-B). Distribution analysis suggested","PeriodicalId":9495,"journal":{"name":"Cancer Communications","volume":"44 11","pages":"1311-1315"},"PeriodicalIF":20.1,"publicationDate":"2024-09-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/cac2.12603","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142269900","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Dysfunction of CD8+ T cells in the tumor microenvironment (TME) contributes to tumor immune escape and immunotherapy tolerance. The effects of hormones such as leptin, steroid hormones, and glucocorticoids on T cell function have been reported previously. However, the mechanism underlying thyroid-stimulating hormone (TSH)/thyroid-stimulating hormone receptor (TSHR) signaling in CD8+ T cell exhaustion and tumor immune evasion remain poorly understood. This study was aimed at investigating the effects of TSH/TSHR signaling on the function of CD8+ T cells and immune evasion in colorectal cancer (CRC).
Methods
TSHR expression levels in CD8+ T cells were assessed with immunofluorescence and flow cytometry. Functional investigations involved manipulation of TSHR expression in cellular and mouse models to study its role in CD8+ T cells. Mechanistic insights were mainly gained through RNA-sequencing, Western blotting, chromatin immunoprecipitation and luciferase activity assay. Immunofluorescence, flow cytometry and Western blotting were used to investigate the source of TSH and TSHR in CRC tissues.
Results
TSHR was highly expressed in cancer cells and CD8+ T cells in CRC tissues. TSH/TSHR signaling was identified as the intrinsic pathway promoting CD8+ T cell exhaustion. Conditional deletion of TSHR in CD8+ tumor-infiltrating lymphocytes (TILs) improved effector differentiation and suppressed the expression of immune checkpoint receptors such as programmed cell death 1 (PD-1) and hepatitis A virus cellular receptor 2 (HAVCR2 or TIM3) through the protein kinase A (PKA)/cAMP-response element binding protein (CREB) signaling pathway. CRC cells secreted TSHR via exosomes to increase the TSHR level in CD8+ T cells, resulting in immunosuppression in the TME. Myeloid-derived suppressor cells (MDSCs) was the main source of TSH within the TME. Low expression of TSHR in CRC was a predictor of immunotherapy response.
Conclusions
The present findings highlighted the role of endogenous TSH/TSHR signaling in CD8+ T cell exhaustion and immune evasion in CRC. TSHR may be suitable as a predictive and therapeutic biomarker in CRC immunotherapy.
肿瘤微环境（TME）中的 CD8+ T 细胞功能失调会导致肿瘤免疫逃逸和免疫治疗耐受。瘦素、类固醇激素和糖皮质激素等激素对T细胞功能的影响已有报道。然而，促甲状腺激素（TSH）/促甲状腺激素受体（TSHR）信号在CD8+ T细胞衰竭和肿瘤免疫逃避中的作用机制仍不甚明了。本研究旨在探讨TSH/TSHR信号对CD8+ T细胞功能和结直肠癌（CRC）免疫逃避的影响。
{"title":"Local TSH/TSHR signaling promotes CD8+ T cell exhaustion and immune evasion in colorectal carcinoma","authors":"Sisi Zeng, Huiling Hu, Zhiyang Li, Qi Hu, Rong Shen, Mingzhou Li, Yunshi Liang, Zuokang Mao, Yandong Zhang, Wanqi Zhan, Qin Zhu, Feifei Wang, Jianbiao Xiao, Bohan Xu, Guanglong Liu, Yanan Wang, Bingsong Li, Shaowan Xu, Zhaowen Zhang, Ceng Zhang, Zhizhang Wang, Li Liang","doi":"10.1002/cac2.12605","DOIUrl":"10.1002/cac2.12605","url":null,"abstract":"<div>\u0000 \u0000 \u0000 <section>\u0000 \u0000 <h3> Background</h3>\u0000 \u0000 <p>Dysfunction of CD8<sup>+</sup> T cells in the tumor microenvironment (TME) contributes to tumor immune escape and immunotherapy tolerance. The effects of hormones such as leptin, steroid hormones, and glucocorticoids on T cell function have been reported previously. However, the mechanism underlying thyroid-stimulating hormone (TSH)/thyroid-stimulating hormone receptor (TSHR) signaling in CD8<sup>+</sup> T cell exhaustion and tumor immune evasion remain poorly understood. This study was aimed at investigating the effects of TSH/TSHR signaling on the function of CD8<sup>+</sup> T cells and immune evasion in colorectal cancer (CRC).</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Methods</h3>\u0000 \u0000 <p>TSHR expression levels in CD8<sup>+</sup> T cells were assessed with immunofluorescence and flow cytometry. Functional investigations involved manipulation of TSHR expression in cellular and mouse models to study its role in CD8<sup>+</sup> T cells. Mechanistic insights were mainly gained through RNA-sequencing, Western blotting, chromatin immunoprecipitation and luciferase activity assay. Immunofluorescence, flow cytometry and Western blotting were used to investigate the source of TSH and TSHR in CRC tissues.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Results</h3>\u0000 \u0000 <p>TSHR was highly expressed in cancer cells and CD8<sup>+</sup> T cells in CRC tissues. TSH/TSHR signaling was identified as the intrinsic pathway promoting CD8<sup>+</sup> T cell exhaustion. Conditional deletion of TSHR in CD8<sup>+</sup> tumor-infiltrating lymphocytes (TILs) improved effector differentiation and suppressed the expression of immune checkpoint receptors such as programmed cell death 1 (PD-1) and hepatitis A virus cellular receptor 2 (HAVCR2 or TIM3) through the protein kinase A (PKA)/cAMP-response element binding protein (CREB) signaling pathway. CRC cells secreted TSHR via exosomes to increase the TSHR level in CD8<sup>+</sup> T cells, resulting in immunosuppression in the TME. Myeloid-derived suppressor cells (MDSCs) was the main source of TSH within the TME. Low expression of TSHR in CRC was a predictor of immunotherapy response.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Conclusions</h3>\u0000 \u0000 <p>The present findings highlighted the role of endogenous TSH/TSHR signaling in CD8<sup>+</sup> T cell exhaustion and immune evasion in CRC. TSHR may be suitable as a predictive and therapeutic biomarker in CRC immunotherapy.</p>\u0000 </section>\u0000 </div>","PeriodicalId":9495,"journal":{"name":"Cancer Communications","volume":"44 11","pages":"1287-1310"},"PeriodicalIF":20.1,"publicationDate":"2024-09-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/cac2.12605","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142269897","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
In the era of immunotherapy, neoadjuvant immunochemotherapy (NAIC) for the treatment of locally advanced esophageal squamous cell carcinoma (ESCC) is used clinically but lacks of high-level clinical evidence. This study aimed to compare the safety and long-term efficacy of NAIC followed by minimally invasive esophagectomy (MIE) with those of neoadjuvant chemotherapy (NAC) followed by MIE.
Methods
A prospective, single-center, open-label, randomized phase III clinical trial was conducted at Henan Cancer Hospital, Zhengzhou, China. Patients were randomly assigned to receive either neoadjuvant toripalimab (240 mg) plus paclitaxel (175 mg/m2) + cisplatin (75 mg/m2) (toripalimab group) or paclitaxel + cisplatin alone (chemotherapy group) every 3 weeks for 2 cycles. After surgery, the toripalimab group received toripalimab (240 mg every 3 weeks for up to 6 months). The primary endpoint was event-free survival (EFS). The pathological complete response (pCR) and overall survival (OS) were key secondary endpoints. Adverse events (AEs) and quality of life were also assessed.
Results
Between May 15, 2020 and August 13, 2021, 252 ESCC patients ranging from T1N1-3M0 to T2-3N0-3M0 were enrolled for interim analysis, with 127 in the toripalimab group and 125 in the chemotherapy group. The 1-year EFS rate was 77.9% in the toripalimab group compared to 64.3% in the chemotherapy group (hazard ratio [HR] = 0.62; 95% confidence interval [CI] = 0.39 to 1.00; P = 0.05). The 1-year OS rates were 94.1% and 83.0% in the toripalimab and chemotherapy groups, respectively (HR = 0.48; 95% CI = 0.24 to 0.97; P = 0.037). The patients in the toripalimab group had a higher pCR rate (18.6% vs. 4.6%; P = 0.001). The rates of postoperative Clavien-Dindo grade IIIb or higher morbidity were 9.8% in the toripalimab group and 6.8% in the chemotherapy group, with no significant difference observed (P = 0.460). The rates of grade 3 or 4 treatment-related AEs did not differ between the two groups (12.5% versus 12.4%).
Conclusions
The interim results of this ongoing trial showed that in resectable ESCC, the addition of perioperative toripalimab to NAC is safe, may improve OS and might change the standard treatment in the future.
{"title":"Perioperative toripalimab plus neoadjuvant chemotherapy might improve outcomes in resectable esophageal cancer: an interim analysis of a phase III randomized clinical trial","authors":"Yan Zheng, Guanghui Liang, Dongfeng Yuan, Xianben Liu, Yufeng Ba, Zimin Qin, Sining Shen, Zhenxuan Li, Haibo Sun, Baoxing Liu, Quanli Gao, Peng Li, Zongfei Wang, Shilei Liu, Jianping Zhu, Haoran Wang, Haibo Ma, Zhenzhen Liu, Fei Zhao, Jun Zhang, He Zhang, Daoyuan Wu, Jinrong Qu, Jie Ma, Peng Zhang, Wenjie Ma, Ming Yan, Yongkui Yu, Qing Li, Jiangong Zhang, Wenqun Xing","doi":"10.1002/cac2.12604","DOIUrl":"10.1002/cac2.12604","url":null,"abstract":"<div>\u0000 \u0000 \u0000 <section>\u0000 \u0000 <h3> Background</h3>\u0000 \u0000 <p>In the era of immunotherapy, neoadjuvant immunochemotherapy (NAIC) for the treatment of locally advanced esophageal squamous cell carcinoma (ESCC) is used clinically but lacks of high-level clinical evidence. This study aimed to compare the safety and long-term efficacy of NAIC followed by minimally invasive esophagectomy (MIE) with those of neoadjuvant chemotherapy (NAC) followed by MIE.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Methods</h3>\u0000 \u0000 <p>A prospective, single-center, open-label, randomized phase III clinical trial was conducted at Henan Cancer Hospital, Zhengzhou, China. Patients were randomly assigned to receive either neoadjuvant toripalimab (240 mg) plus paclitaxel (175 mg/m<sup>2</sup>) + cisplatin (75 mg/m<sup>2</sup>) (toripalimab group) or paclitaxel + cisplatin alone (chemotherapy group) every 3 weeks for 2 cycles. After surgery, the toripalimab group received toripalimab (240 mg every 3 weeks for up to 6 months). The primary endpoint was event-free survival (EFS). The pathological complete response (pCR) and overall survival (OS) were key secondary endpoints. Adverse events (AEs) and quality of life were also assessed.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Results</h3>\u0000 \u0000 <p>Between May 15, 2020 and August 13, 2021, 252 ESCC patients ranging from T1N1-3M0 to T2-3N0-3M0 were enrolled for interim analysis, with 127 in the toripalimab group and 125 in the chemotherapy group. The 1-year EFS rate was 77.9% in the toripalimab group compared to 64.3% in the chemotherapy group (hazard ratio [HR] = 0.62; 95% confidence interval [CI] = 0.39 to 1.00; <i>P</i> = 0.05). The 1-year OS rates were 94.1% and 83.0% in the toripalimab and chemotherapy groups, respectively (HR = 0.48; 95% CI = 0.24 to 0.97; <i>P =</i> 0.037). The patients in the toripalimab group had a higher pCR rate (18.6% vs. 4.6%; <i>P</i> = 0.001). The rates of postoperative Clavien-Dindo grade IIIb or higher morbidity were 9.8% in the toripalimab group and 6.8% in the chemotherapy group, with no significant difference observed (<i>P</i> = 0.460). The rates of grade 3 or 4 treatment-related AEs did not differ between the two groups (12.5% versus 12.4%).</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Conclusions</h3>\u0000 \u0000 <p>The interim results of this ongoing trial showed that in resectable ESCC, the addition of perioperative toripalimab to NAC is safe, may improve OS and might change the standard treatment in the future.</p>\u0000 </section>\u0000 </div>","PeriodicalId":9495,"journal":{"name":"Cancer Communications","volume":"44 10","pages":"1214-1227"},"PeriodicalIF":20.1,"publicationDate":"2024-09-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/cac2.12604","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142104685","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Nelleke Pietronella Maria Brouwer, Ayse Selcen Oguz Erdogan, Shannon van Vliet, Natasja Rutgers, Nikki Knijn, Gesina van Lijnschoten, Jessica Juliana Tan, Johannes Hendrik Willem de Wilt, Niek Hugen, Gina Brown, Femke Simmer, Iris Dionne Nagtegaal
<p>Currently, lymph node metastases (LNM) are seen as the gateway to distant metastases in CRC and play a crucial role in the Tumor Node Metastasis (TNM) staging system [<span>1, 2</span>]. Tumor deposits (TD) have been identified as another histological feature with a strong prognostic impact but are currently only deemed clinically relevant in the absence of LNM [<span>2, 3</span>]. TD are clusters of tumor cells in the fat surrounding the bowel and are often associated with nerves, vessels and lymphatic tissue, giving the cancer cells access to multiple routes of spread [<span>4</span>].</p><p>To study whether TD could indeed form an alternative gateway to distant metastases, we have used polyG-based phylogenetics on formalin-fixed paraffin-embedded (FFPE) tissue to investigate the role of histologically defined TD and LNM in CRC evolution and distant metastatic spread to the liver and peritoneum.</p><p>We collected data from patients who were diagnosed with colorectal liver or peritoneal metastases between January 2015 and January 2022 and not previously treated with chemotherapy. DNA was isolated from the TD and LNM (Figure 1A), normal tissue (which was sampled at the edge of the resection specimen) and distant metastases. Three distinct tissue parts of the primary tumor were sampled to account for intra-tumor heterogeneity (Figure 1B), yielding a total of 480 samples (Supplementary Table S1). Polymerase chain reaction (PCR) was used to genotype up to 24 polyG regions for every sample (Supplementary Table S2). Sequentially, phylogenetic trees were constructed based on the peak distribution of all PCR results from the polyG regions using an analysis pipeline previously developed by Naxerova et al. in R software (version 4.3.1) [<span>5</span>]. Phylogenetic trees are graphical representations of the evolutionary relationship between biological entities, in this case, the different tissue samples. After quality control of PCR results (i.e., poor quality DNA), impurity (i.e., contamination of samples with non-tumorous cells, Supplementary Figure S1), and branching confidence (i.e., values < 50% were deemed unreliable), 47 CRC patients with a total of 43 individual liver metastases and 30 individual peritoneal metastases were included in the final results (Supplementary Table S3-S5). The distribution of origins (TD, LNM, primary tumor or a mix of these) was compared between the group of liver and the group of peritoneal metastases using Fisher's exact test. Potential confounding clinicopathological factors were analyzed using the Kruskal-Wallis of Fisher's exact test. <i>P</i> values < 0.05 were considered significant. Full descriptions of the materials and methods are provided in the Supplementary Materials.</p><p>Phylogenetic analysis showed that the primary tumor, TD, and LNM could be possible origins of liver metastases. An exemplary phylogenetic tree is shown in Figure 1C, where different subclones gave rise to different LNMs, and sev
在系统发育分析中，LNMs 和 TDs 都是肝转移的可能途径，并且有各自进入体循环的方式。对于淋巴结转移瘤，小鼠研究表明，肿瘤细胞既可以侵入淋巴结周围的小血管，也可以穿过淋巴系统，在胸导管处进入体循环[8]。尽管如此，关于其确切机制仍存在广泛争议，而在人类中，其机制仍不清楚。对于 TDs 而言，更广泛的看法是它们可以进入血液循环，因为这反映在它们的组织学中[4]。与文献一致，我们的研究显示 69% 的 TD 与肝转移有关，其中存在血管成分（补充图 S4）。对于腹膜转移瘤，有人提出了侵袭-转移级联的替代方案，即肿瘤细胞更直接地向腹膜迁移[7]。我们曾发现，与 LNM 相比，TD 中肿瘤细胞主动迁移至腹膜并侵入腹膜所需的分子表型表达过高[9]。因此，有能力形成TD的肿瘤细胞也有能力通过浆膜表面进一步迁移并侵入腹膜，这一点很可能比LNM中的肿瘤细胞更强。首先，虽然所有病例都符合每例 CRC 淋巴结取样超过 12 个的质量标准，而且 TD 由两名病理学家和一名专家研究员进行评分，但在切除标本取样过程中仍有可能漏掉一些 TD 或 LNM。其次，建议所有系统发育研究都使用不同的方法（如全基因组或外显子组测序）进行验证，以显示结果是否具有普遍性和稳健性[10]。第三，由于时间和经费的限制，本研究只包括了 CRC 最常见的转移部位--肝脏和腹膜。总之，通过系统发育分析，本研究表明 TDs 和 LNMs 都与 CRC 的肝脏或腹膜转移有关。此外，每个转移部位的转移来源也不同，肝脏转移与TDs和LNMs的关系相同，而腹膜转移与TDs的关系明显更多。因此，未来的研究应重点关注 TD 患者发生腹膜转移的风险是否会增加，因为这可能会影响随访和治疗决策。此外，由于我们发现大量肝转移灶和腹膜转移灶与 TDs 有关，因此应该质疑目前在对 CRC 患者进行分期时将 TDs 视为不如 LNM 重要的方法是否合理。我们建议，TDs 应得到更多关注，将其作为与 LNMs 同等重要的结节类别，并在未来的研究中继续登记：Gina Brown、Femke Simmer、Iris Dionne Nagtegaal。方法论：Nelleke Pietronella Maria Brouwer、Ayse Selcen Oguz Erdogan、Niek Hugen、Femke Simmer、Iris Dionne Nagtegaal。资金获取：Gina Brown、Iris Dionne Nagtegaal。数据采集与分析Nelleke Pietronella Maria Brouwer、Ayse Selcen Oguz Erdogan、Shannon van Vliet、Natasja Rutgers。统计分析：Nelleke Pietronella Maria Brouwer、Ayse Selcen Oguz Erdogan、Shannon van Vliet、Natasja Rutgers、Femke Simmer。材料支持Nikki Knijn、Gesina van Lijnschoten、Jessica Juliana Tan、Gina Brown。写作-原稿：Nelleke Pietronella Maria Brouwer、Ayse Selcen Oguz Erdogan、Niek Hugen、Femke Simmer、Iris Dionne Nagtegaal。撰稿-审稿-编辑Nelleke Pietronella Maria Brouwer、Ayse Selcen Oguz Erdogan、Shannon van Vliet、Natasja Rutgers、Nikki Knijn、Gesina van Lijnschoten、Jessica Juliana Tan、Johannes Hendrik Willem de Wilt、Niek Hugen、Gina Brown、Femke Simmer、Iris Dionne Nagtegaal。本研究得到了荷兰癌症协会（KUN 2019-12640）的支持。本研究根据荷兰 "人体组织和医学研究联合会"（Federa, Human Tissue and Medical Research：本研究根据荷兰《联邦人类组织和医学研究：负责任使用行为准则（2011）》的规定进行，无需患者知情同意。本研究已获得拉德布鲁德大学伦理委员会（CMO）的批准（批准号2020-7172）。
{"title":"Unraveling the routes to distant metastases in colorectal cancer: Tumor deposits and lymph node metastases as the gateway","authors":"Nelleke Pietronella Maria Brouwer, Ayse Selcen Oguz Erdogan, Shannon van Vliet, Natasja Rutgers, Nikki Knijn, Gesina van Lijnschoten, Jessica Juliana Tan, Johannes Hendrik Willem de Wilt, Niek Hugen, Gina Brown, Femke Simmer, Iris Dionne Nagtegaal","doi":"10.1002/cac2.12598","DOIUrl":"10.1002/cac2.12598","url":null,"abstract":"<p>Currently, lymph node metastases (LNM) are seen as the gateway to distant metastases in CRC and play a crucial role in the Tumor Node Metastasis (TNM) staging system [<span>1, 2</span>]. Tumor deposits (TD) have been identified as another histological feature with a strong prognostic impact but are currently only deemed clinically relevant in the absence of LNM [<span>2, 3</span>]. TD are clusters of tumor cells in the fat surrounding the bowel and are often associated with nerves, vessels and lymphatic tissue, giving the cancer cells access to multiple routes of spread [<span>4</span>].</p><p>To study whether TD could indeed form an alternative gateway to distant metastases, we have used polyG-based phylogenetics on formalin-fixed paraffin-embedded (FFPE) tissue to investigate the role of histologically defined TD and LNM in CRC evolution and distant metastatic spread to the liver and peritoneum.</p><p>We collected data from patients who were diagnosed with colorectal liver or peritoneal metastases between January 2015 and January 2022 and not previously treated with chemotherapy. DNA was isolated from the TD and LNM (Figure 1A), normal tissue (which was sampled at the edge of the resection specimen) and distant metastases. Three distinct tissue parts of the primary tumor were sampled to account for intra-tumor heterogeneity (Figure 1B), yielding a total of 480 samples (Supplementary Table S1). Polymerase chain reaction (PCR) was used to genotype up to 24 polyG regions for every sample (Supplementary Table S2). Sequentially, phylogenetic trees were constructed based on the peak distribution of all PCR results from the polyG regions using an analysis pipeline previously developed by Naxerova et al. in R software (version 4.3.1) [<span>5</span>]. Phylogenetic trees are graphical representations of the evolutionary relationship between biological entities, in this case, the different tissue samples. After quality control of PCR results (i.e., poor quality DNA), impurity (i.e., contamination of samples with non-tumorous cells, Supplementary Figure S1), and branching confidence (i.e., values < 50% were deemed unreliable), 47 CRC patients with a total of 43 individual liver metastases and 30 individual peritoneal metastases were included in the final results (Supplementary Table S3-S5). The distribution of origins (TD, LNM, primary tumor or a mix of these) was compared between the group of liver and the group of peritoneal metastases using Fisher's exact test. Potential confounding clinicopathological factors were analyzed using the Kruskal-Wallis of Fisher's exact test. <i>P</i> values < 0.05 were considered significant. Full descriptions of the materials and methods are provided in the Supplementary Materials.</p><p>Phylogenetic analysis showed that the primary tumor, TD, and LNM could be possible origins of liver metastases. An exemplary phylogenetic tree is shown in Figure 1C, where different subclones gave rise to different LNMs, and sev","PeriodicalId":9495,"journal":{"name":"Cancer Communications","volume":"44 10","pages":"1209-1213"},"PeriodicalIF":20.1,"publicationDate":"2024-08-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/cac2.12598","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142055045","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Concurrent chemoradiotherapy (CCRT) is the standard treatment for locally advanced esophageal squamous cell carcinoma (ESCC). However, the optimal radiotherapy regimen, particularly in terms of total dose and planned range of irradiation field, remains unclear. This phase III clinical trial aimed to compare the survival benefits between different radiation doses and different target fields.
Methods
This trial compared two aspects of radiation treatment, total dose and field, using a two-by-two factorial design. The high-dose (HD) group received 59.4 Gy radiation, and the standard-dose (SD) group received 50.4 Gy. The involved field irradiation (IFI) group and elective nodal irradiation (ENI) group adopted different irradiation ranges. The participants were assigned to one of the four groups (HD+ENI, HD+IFI, SD+ENI and SD+IFI). The primary endpoint was overall survival (OS), and the secondary endpoints included progression-free survival (PFS). The synergy indexwas used to measure the interaction effect between dose and field.
Results
The interaction analysis did not reveal significant synergistic effects between the dose and irradiation field. In comparison to the target field, patients in IFI or ENI showed similar OS (hazard ratio [HR] = 0.99, 95% CI: 0.80-1.23, p = 0.930) and PFS (HR = 1.02, 95% CI: 0.82–1.25). The HD treatment did not show significantly prolonged OS compared with SD (HR = 0.90, 95% CI: 0.72–1.11, p = 0.318), but it suggested improved PFS (25.2 months to 18.0 months). Among the four groups, the HD+IFI group presented the best survival, while the SD+IFI group had the worst prognosis. No significant difference in the occurrence of severe adverse events was found in dose or field comparisons.
Conclusions
IFI demonstrated similar treatment efficacy to ENI in CCRT of ESCC. The HD demonstrated improved PFS, but did not significantly improve OS. The dose escalation based on IFI (HD+IFI) showed better therapeutic efficacy than the current recommendation (SD+ENI) and is worth further validation.
{"title":"Concurrent chemoradiotherapyof different radiation doses and different irradiation fields for locally advanced thoracic esophageal squamous cell carcinoma: A randomized, multicenter, phase III clinical trial","authors":"Jian Zhang, Minghao Li, Kaixian Zhang, Anping Zheng, Guang Li, Wei Huang, Shaoshui Chen, Xiangming Chen, Xiaomin Li, Yanxing Sheng, Xinchen Sun, Liping Liu, Xiaowei Liu, Jie Li, Jun Wang, Hong Ge, Shucheng Ye, Qingsong Pang, Xianwen Zhang, Shengbin Dai, Richard Yu, Wendong Gu, Mingming Dai, Gaowa Siqin, Yunwei Han, Xiaolin Ge, Xin Yuan, Yongjing Yang, Haiwen Zhu, Juan Pu, Lihua Dong, Xiangdong Sun, Jundong Zhou, Weidong Mao, Fei Gao, Haiqun Lin, Heyi Gong, Tao Zhou, Zhenjiang Li, Hongsheng Li, Zhongtang Wang, Baosheng Li","doi":"10.1002/cac2.12601","DOIUrl":"10.1002/cac2.12601","url":null,"abstract":"<div>\u0000 \u0000 \u0000 <section>\u0000 \u0000 <h3> Background</h3>\u0000 \u0000 <p>Concurrent chemoradiotherapy (CCRT) is the standard treatment for locally advanced esophageal squamous cell carcinoma (ESCC). However, the optimal radiotherapy regimen, particularly in terms of total dose and planned range of irradiation field, remains unclear. This phase III clinical trial aimed to compare the survival benefits between different radiation doses and different target fields.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Methods</h3>\u0000 \u0000 <p>This trial compared two aspects of radiation treatment, total dose and field, using a two-by-two factorial design. The high-dose (HD) group received 59.4 Gy radiation, and the standard-dose (SD) group received 50.4 Gy. The involved field irradiation (IFI) group and elective nodal irradiation (ENI) group adopted different irradiation ranges. The participants were assigned to one of the four groups (HD+ENI, HD+IFI, SD+ENI and SD+IFI). The primary endpoint was overall survival (OS), and the secondary endpoints included progression-free survival (PFS). The synergy indexwas used to measure the interaction effect between dose and field.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Results</h3>\u0000 \u0000 <p>The interaction analysis did not reveal significant synergistic effects between the dose and irradiation field. In comparison to the target field, patients in IFI or ENI showed similar OS (hazard ratio [HR] = 0.99, 95% CI: 0.80-1.23, <i>p</i> = 0.930) and PFS (HR = 1.02, 95% CI: 0.82–1.25). The HD treatment did not show significantly prolonged OS compared with SD (HR = 0.90, 95% CI: 0.72–1.11, <i>p</i> = 0.318), but it suggested improved PFS (25.2 months to 18.0 months). Among the four groups, the HD+IFI group presented the best survival, while the SD+IFI group had the worst prognosis. No significant difference in the occurrence of severe adverse events was found in dose or field comparisons.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Conclusions</h3>\u0000 \u0000 <p>IFI demonstrated similar treatment efficacy to ENI in CCRT of ESCC. The HD demonstrated improved PFS, but did not significantly improve OS. The dose escalation based on IFI (HD+IFI) showed better therapeutic efficacy than the current recommendation (SD+ENI) and is worth further validation.</p>\u0000 </section>\u0000 </div>","PeriodicalId":9495,"journal":{"name":"Cancer Communications","volume":"44 10","pages":"1173-1188"},"PeriodicalIF":20.1,"publicationDate":"2024-08-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/cac2.12601","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142003690","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Maxim Noeraparast, Katarina Krajina, Renate Pichler, Dora Niedersüß-Beke, Shahrokh F Shariat, Viktor Grünwald, Sascha Ahyai, Martin Pichler
In this review, we revisit the pivotal role of fibroblast growth factor receptor 3 (FGFR3) in bladder cancer (BLCA), underscoring its prevalence in both non-muscle-invasive and muscle-invasive forms of the disease. FGFR3 mutations in up to half of BLCAs play a well-established role in tumorigenesis, shaping distinct tumor initiation patterns and impacting the tumor microenvironment (TME). Emphasizing the importance of considering epithelial-mesenchymal transition profile and TME status, we revisit their relevance in predicting responses to immune checkpoint inhibitors in FGFR3-mutated BLCAs. This writing highlights the initially promising yet transient efficacy of the FGFR inhibitor Erdafitinib on FGFR3-mutated BLCA, stressing the pressing need to unravel resistance mechanisms and identify co-targets for future combinatorial studies. A thorough analysis of recent preclinical and clinical evidence reveals resistance mechanisms, including secondary mutations, epigenetic alterations in pathway effectors, phenotypic heterogeneity, and population-specific variations within FGFR3 mutational status. Lastly, we discuss the potential of combinatorial treatments and concepts like synthetic lethality for discovering more effective targeted therapies against FGFR3-mutated BLCA.
{"title":"FGFR3 alterations in bladder cancer: Sensitivity and resistance to targeted therapies","authors":"Maxim Noeraparast, Katarina Krajina, Renate Pichler, Dora Niedersüß-Beke, Shahrokh F Shariat, Viktor Grünwald, Sascha Ahyai, Martin Pichler","doi":"10.1002/cac2.12602","DOIUrl":"10.1002/cac2.12602","url":null,"abstract":"<p>In this review, we revisit the pivotal role of fibroblast growth factor receptor 3 (FGFR3) in bladder cancer (BLCA), underscoring its prevalence in both non-muscle-invasive and muscle-invasive forms of the disease. FGFR3 mutations in up to half of BLCAs play a well-established role in tumorigenesis, shaping distinct tumor initiation patterns and impacting the tumor microenvironment (TME). Emphasizing the importance of considering epithelial-mesenchymal transition profile and TME status, we revisit their relevance in predicting responses to immune checkpoint inhibitors in FGFR3-mutated BLCAs. This writing highlights the initially promising yet transient efficacy of the FGFR inhibitor Erdafitinib on FGFR3-mutated BLCA, stressing the pressing need to unravel resistance mechanisms and identify co-targets for future combinatorial studies. A thorough analysis of recent preclinical and clinical evidence reveals resistance mechanisms, including secondary mutations, epigenetic alterations in pathway effectors, phenotypic heterogeneity, and population-specific variations within FGFR3 mutational status. Lastly, we discuss the potential of combinatorial treatments and concepts like synthetic lethality for discovering more effective targeted therapies against FGFR3-mutated BLCA.</p>","PeriodicalId":9495,"journal":{"name":"Cancer Communications","volume":"44 10","pages":"1189-1208"},"PeriodicalIF":20.1,"publicationDate":"2024-08-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/cac2.12602","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142003691","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Yuji Uehara, Shumei Kato, Daisuke Nishizaki, Hirotaka Miyashita, Suzanna Lee, Mary K. Nesline, Sarabjot Pabla, Jeffrey M. Conroy, Paul DePietro, Heidi Ko, Jason K. Sicklick, Razelle Kurzrock
<p>4-1BB, a member of the tumor necrosis factor receptor superfamily, is an important co-stimulatory molecule regulating the activity of immune cells across a range of physiological and pathological processes, which culminates in a potent immune response (Figure 1A and B) [<span>1, 2</span>]. Numerous clinical trials have been conducted utilizing 4–1BB agonists (Supplemental Table S1); however, previous and ongoing 4-1BB agonist trials are being conducted without biomarker selection, which potentially explains their modest efficacy. Interestingly, several studies suggest the potential value of utilizing transcriptomics in addition to genomics to identify the unique immunologic signature of individual tumors [<span>3-7</span>].</p><p>Herein, we explore the landscape of 4–1BB transcriptomic profiles in 514 patients, including 489 with advanced/metastatic cancers and clinical annotation, and we discuss the potential therapeutic implications of the observed patterns and heterogeneity. The study methods are provided in the Supplementary File.</p><p>There were 514 tumors reflecting 31 different cancer types evaluated (Supplemental Table S2). Their median age was 61 (range, 24-93) years; 310 (60.3%) were women. The most frequent tumor types assessed were colorectal cancer (<i>n</i> = 140 samples). Of the 514 patients, 489 had confirmed metastatic or locally advanced disease, but the dates of metastatic disease for 25 patients were not documented. Overall, 489 patients with advanced/metastatic disease had fully evaluable clinical correlative data (Figure 1C). In total, 217 patients received ICIs; 199 received anti-programmed cell death 1 (PD-1)/ programmed death-ligand 1 (PD-L1) monotherapy, 2 received anti-cytotoxic T-lymphocyte-associated protein 4 (CTLA-4) monotherapy, and 16 received a combination of anti-PD-1/PD-L1 and anti-CTLA-4. The remaining 272 patients never received immunotherapy.</p><p>Figure 1D demonstrates the variations in 4-1BB RNA expression across different cancer types: 4-1BB ribonucleic acid (RNA) expression was classified as “high” (75-100th percentile), “moderate” (25-74th percentile), and “low” (0-24th percentile). Among all cancers (<i>n</i> = 514), 77 (15.0%) had high, 268 (52.1%) had moderate, and 169 (32.9%) had low 4-1BB expression. Small intestine and ovarian cancers most frequently had high 4-1BB RNA expression (25.0% and 20.9% of tumors, respectively).</p><p>To identify the patient population who might theoretically benefit the most from 4-1BB agonism, the proportion of patients having high 4-1BB expression along with low/moderate 4-1BB ligand (4-1BBL) expression was assessed in malignancies that had more than 20 representative samples (from a biologic point of view, high receptor with low/moderate ligand might be most amenable to treatment with 4-1BB agonists in the clinic). Malignancies with the highest proportion of patients having both high 4-1BB expression and low/moderate 4-1BBL expression were ovarian and pancreatic
{"title":"4-1BB transcriptomic expression patterns across malignancies: Implications for clinical trials of 4-1BB agonists","authors":"Yuji Uehara, Shumei Kato, Daisuke Nishizaki, Hirotaka Miyashita, Suzanna Lee, Mary K. Nesline, Sarabjot Pabla, Jeffrey M. Conroy, Paul DePietro, Heidi Ko, Jason K. Sicklick, Razelle Kurzrock","doi":"10.1002/cac2.12592","DOIUrl":"10.1002/cac2.12592","url":null,"abstract":"<p>4-1BB, a member of the tumor necrosis factor receptor superfamily, is an important co-stimulatory molecule regulating the activity of immune cells across a range of physiological and pathological processes, which culminates in a potent immune response (Figure 1A and B) [<span>1, 2</span>]. Numerous clinical trials have been conducted utilizing 4–1BB agonists (Supplemental Table S1); however, previous and ongoing 4-1BB agonist trials are being conducted without biomarker selection, which potentially explains their modest efficacy. Interestingly, several studies suggest the potential value of utilizing transcriptomics in addition to genomics to identify the unique immunologic signature of individual tumors [<span>3-7</span>].</p><p>Herein, we explore the landscape of 4–1BB transcriptomic profiles in 514 patients, including 489 with advanced/metastatic cancers and clinical annotation, and we discuss the potential therapeutic implications of the observed patterns and heterogeneity. The study methods are provided in the Supplementary File.</p><p>There were 514 tumors reflecting 31 different cancer types evaluated (Supplemental Table S2). Their median age was 61 (range, 24-93) years; 310 (60.3%) were women. The most frequent tumor types assessed were colorectal cancer (<i>n</i> = 140 samples). Of the 514 patients, 489 had confirmed metastatic or locally advanced disease, but the dates of metastatic disease for 25 patients were not documented. Overall, 489 patients with advanced/metastatic disease had fully evaluable clinical correlative data (Figure 1C). In total, 217 patients received ICIs; 199 received anti-programmed cell death 1 (PD-1)/ programmed death-ligand 1 (PD-L1) monotherapy, 2 received anti-cytotoxic T-lymphocyte-associated protein 4 (CTLA-4) monotherapy, and 16 received a combination of anti-PD-1/PD-L1 and anti-CTLA-4. The remaining 272 patients never received immunotherapy.</p><p>Figure 1D demonstrates the variations in 4-1BB RNA expression across different cancer types: 4-1BB ribonucleic acid (RNA) expression was classified as “high” (75-100th percentile), “moderate” (25-74th percentile), and “low” (0-24th percentile). Among all cancers (<i>n</i> = 514), 77 (15.0%) had high, 268 (52.1%) had moderate, and 169 (32.9%) had low 4-1BB expression. Small intestine and ovarian cancers most frequently had high 4-1BB RNA expression (25.0% and 20.9% of tumors, respectively).</p><p>To identify the patient population who might theoretically benefit the most from 4-1BB agonism, the proportion of patients having high 4-1BB expression along with low/moderate 4-1BB ligand (4-1BBL) expression was assessed in malignancies that had more than 20 representative samples (from a biologic point of view, high receptor with low/moderate ligand might be most amenable to treatment with 4-1BB agonists in the clinic). Malignancies with the highest proportion of patients having both high 4-1BB expression and low/moderate 4-1BBL expression were ovarian and pancreatic","PeriodicalId":9495,"journal":{"name":"Cancer Communications","volume":"44 10","pages":"1168-1172"},"PeriodicalIF":20.1,"publicationDate":"2024-08-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/cac2.12592","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141888502","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
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