Pub Date : 2025-03-11DOI: 10.1158/0008-5472.can-25-1085
Aristeidis Papargyriou, Maximilian Reichert
Metastatic cancer remains a leading cause of cancer-related mortality, with a 5-year survival rate of just 8% for pancreatic ductal adenocarcinoma (PDAC). Among patients with metastatic PDAC, those with liver metastases experience significantly worse outcomes compared to the rare cases of isolated lung metastases. Recent findings by Link and colleagues reveal that these distinct metastatic patterns reflect underlying biological differences beyond established molecular subtypes. Specifically, the authors curated a primary organotropism (pORG) gene signature that is enriched in the liver cohorts. In detail they found that high-pORG/liver-avid tumors are characterized by high replication stress, enriched DNA repair pathways, and an immunosuppressive microenvironment, whereas low-pORG/lung-avid tumors display stronger immune infiltration, higher T cell density and reduce the richness of TCR repertoire, and better survival outcomes. These insights suggest that the clinical pattern of metastasis provides meaningful information about tumor biology and prognosis, complementing current subtype classifications in PDAC.
{"title":"The Biology in the Pattern: Metastatic organotropism and clinical outcome depend on DNA damage response and immune interactions in pancreatic cancer","authors":"Aristeidis Papargyriou, Maximilian Reichert","doi":"10.1158/0008-5472.can-25-1085","DOIUrl":"https://doi.org/10.1158/0008-5472.can-25-1085","url":null,"abstract":"Metastatic cancer remains a leading cause of cancer-related mortality, with a 5-year survival rate of just 8% for pancreatic ductal adenocarcinoma (PDAC). Among patients with metastatic PDAC, those with liver metastases experience significantly worse outcomes compared to the rare cases of isolated lung metastases. Recent findings by Link and colleagues reveal that these distinct metastatic patterns reflect underlying biological differences beyond established molecular subtypes. Specifically, the authors curated a primary organotropism (pORG) gene signature that is enriched in the liver cohorts. In detail they found that high-pORG/liver-avid tumors are characterized by high replication stress, enriched DNA repair pathways, and an immunosuppressive microenvironment, whereas low-pORG/lung-avid tumors display stronger immune infiltration, higher T cell density and reduce the richness of TCR repertoire, and better survival outcomes. These insights suggest that the clinical pattern of metastasis provides meaningful information about tumor biology and prognosis, complementing current subtype classifications in PDAC.","PeriodicalId":9441,"journal":{"name":"Cancer research","volume":"96 1","pages":""},"PeriodicalIF":11.2,"publicationDate":"2025-03-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143599850","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-03-11DOI: 10.1158/0008-5472.can-24-2531
Flaminia Pedretti, Mohmed Abdalfttah, Benedetta Pellegrino, Francesca Mateo, Paula Martínez-Sanz, Andrea Herencia-Ropero, Andreu Òdena, Pau Clavell-Revelles, Giorgia Casali, Heura Domenech, Laia Monserrat, Dražen Papić, Alba Mas Malavila, Anna Pascual-Reguant, Herena Eixarch, Marta Guzman, Olga Rodriguez, Judit Grueso, Sara Simonetti, Roberta Fasani, Paolo Nuciforo, Carmen Espejo, Stefan Florian, Miguel Ángel Pujana, Lara Nonell, Joan Seoane, Viia Valge-Archer, Mark J. O'Connor, Juan C. Nieto, Holger Heyn, Judith Balmaña, Alba Llop-Guevara, Violeta Serra
Homologous recombination deficiency (HRD) contributes to genomic instability and leads to sensitivity to poly ADP-ribose polymerase inhibitors (PARPi). HRD also activates the cyclic GMP–AMP synthase (cGAS)-STimulator of INterferon Genes (STING)-Interferon (IFN) pathway, highlighting the need to understand the impact of cGAS-STING-IFN signaling on PARPi efficacy. In this study, we analyzed a cohort of thirty-five breast cancer (BC) patient-derived xenografts (PDX) and mouse-derived allografts (MDA). PARPi sensitivity correlated with HRD, increased genomic instability, and activation of the cGAS-STING-IFN signaling pathway. Single-cell analyses showed that IFN signaling and IFN-based immune interactions were suppressed in preclinical models with acquired resistance to PARPi, lacking concomitant clonal expansion of functional CD8+ T cells. However, the combination of PARPi and a novel STING agonist (STINGa) increased immune infiltration and resulted in superior antitumor activity in these tumors. Notably, the efficacy of PARPi monotherapy and the combination treatment with a STINGa was dependent on Natural Killer (NK) cells. In agreement, BC patients with BRCA1/BRCA2 mutations and good responses to PARPi showed higher abundancy of CD56+ NK cells in the tumor microenvironment and treatment-engaged CD56bright NK cells in the peripheral immune compartment, compared to those with poor responses. Therefore, these findings propose the combination of PARPi and STINGa as a potential novel strategy to enhance the therapeutic response in patients with acquired PARPi resistance and highlight a pivotal role of NK cells in the PARPi antitumor activity.
{"title":"Harnessing STING Signaling and Natural Killer Cells overcomes PARP Inhibitor Resistance in Homologous Recombination Deficient Breast Cancer","authors":"Flaminia Pedretti, Mohmed Abdalfttah, Benedetta Pellegrino, Francesca Mateo, Paula Martínez-Sanz, Andrea Herencia-Ropero, Andreu Òdena, Pau Clavell-Revelles, Giorgia Casali, Heura Domenech, Laia Monserrat, Dražen Papić, Alba Mas Malavila, Anna Pascual-Reguant, Herena Eixarch, Marta Guzman, Olga Rodriguez, Judit Grueso, Sara Simonetti, Roberta Fasani, Paolo Nuciforo, Carmen Espejo, Stefan Florian, Miguel Ángel Pujana, Lara Nonell, Joan Seoane, Viia Valge-Archer, Mark J. O'Connor, Juan C. Nieto, Holger Heyn, Judith Balmaña, Alba Llop-Guevara, Violeta Serra","doi":"10.1158/0008-5472.can-24-2531","DOIUrl":"https://doi.org/10.1158/0008-5472.can-24-2531","url":null,"abstract":"Homologous recombination deficiency (HRD) contributes to genomic instability and leads to sensitivity to poly ADP-ribose polymerase inhibitors (PARPi). HRD also activates the cyclic GMP–AMP synthase (cGAS)-STimulator of INterferon Genes (STING)-Interferon (IFN) pathway, highlighting the need to understand the impact of cGAS-STING-IFN signaling on PARPi efficacy. In this study, we analyzed a cohort of thirty-five breast cancer (BC) patient-derived xenografts (PDX) and mouse-derived allografts (MDA). PARPi sensitivity correlated with HRD, increased genomic instability, and activation of the cGAS-STING-IFN signaling pathway. Single-cell analyses showed that IFN signaling and IFN-based immune interactions were suppressed in preclinical models with acquired resistance to PARPi, lacking concomitant clonal expansion of functional CD8+ T cells. However, the combination of PARPi and a novel STING agonist (STINGa) increased immune infiltration and resulted in superior antitumor activity in these tumors. Notably, the efficacy of PARPi monotherapy and the combination treatment with a STINGa was dependent on Natural Killer (NK) cells. In agreement, BC patients with BRCA1/BRCA2 mutations and good responses to PARPi showed higher abundancy of CD56+ NK cells in the tumor microenvironment and treatment-engaged CD56bright NK cells in the peripheral immune compartment, compared to those with poor responses. Therefore, these findings propose the combination of PARPi and STINGa as a potential novel strategy to enhance the therapeutic response in patients with acquired PARPi resistance and highlight a pivotal role of NK cells in the PARPi antitumor activity.","PeriodicalId":9441,"journal":{"name":"Cancer research","volume":"11 1","pages":""},"PeriodicalIF":11.2,"publicationDate":"2025-03-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143599819","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-03-10DOI: 10.1158/0008-5472.can-24-1879
Katherine A. Lawson-Michod, Jeffrey R. Marks, Lindsay J. Collin, David A. Nix, Natalie R. Davidson, Chad D. Huff, Yao Yu, Aaron Atkinson, Courtney E. Johnson, Lucas A. Salas, Lauren C. Peres, Casey S. Greene, Joellen M. Schildkraut, Jennifer A. Doherty
Black individuals experience worse survival after a diagnosis of high-grade serous ovarian carcinoma (HGSC) than White individuals and are underrepresented in ovarian cancer research. To date, the understanding of the molecular and genomic heterogeneity of HGSC is based primarily on the evaluation of tumors from White individuals. In the present study, we performed whole exome sequencing on HGSC samples from 211 Black patients to identify significantly mutated genes and characterize mutational signatures, assessing their distributions by gene expression subtypes. The occurrence and frequency of somatic mutations and signatures by self-reported race were compared to historical data from The Cancer Genome Atlas (TCGA). Despite technical differences (e.g., formalin-fixed vs. fresh-frozen tissue), the distribution of mutations and their variant classifications for major HGSC genes were nearly identical across study populations. However, de novo significantly mutated gene analysis identified genes not previously reported in the TCGA analysis, including the oncogene KRAS and the potential tumor suppressor OBSCN. The prevalence of the homologous recombination deficiency signature was higher among Black individuals with the immunoreactive gene expression subtype compared with the mesenchymal and proliferative subtypes. These findings were confirmed by comparing the data from Black patients to 123 White patients with identical tissue collection and processing. Overall, this study suggests that, while most features of HGSC tumor phenotypes are similar in Black and White populations, there may be clinically-relevant differences. If validated, these phenotypes may be important for clinical decision-making and would have been missed by characterizing tumors from White individuals only.
{"title":"Genomic Characterization of High-Grade Serous Ovarian Carcinoma Reveals Distinct Somatic Features in Black Individuals","authors":"Katherine A. Lawson-Michod, Jeffrey R. Marks, Lindsay J. Collin, David A. Nix, Natalie R. Davidson, Chad D. Huff, Yao Yu, Aaron Atkinson, Courtney E. Johnson, Lucas A. Salas, Lauren C. Peres, Casey S. Greene, Joellen M. Schildkraut, Jennifer A. Doherty","doi":"10.1158/0008-5472.can-24-1879","DOIUrl":"https://doi.org/10.1158/0008-5472.can-24-1879","url":null,"abstract":"Black individuals experience worse survival after a diagnosis of high-grade serous ovarian carcinoma (HGSC) than White individuals and are underrepresented in ovarian cancer research. To date, the understanding of the molecular and genomic heterogeneity of HGSC is based primarily on the evaluation of tumors from White individuals. In the present study, we performed whole exome sequencing on HGSC samples from 211 Black patients to identify significantly mutated genes and characterize mutational signatures, assessing their distributions by gene expression subtypes. The occurrence and frequency of somatic mutations and signatures by self-reported race were compared to historical data from The Cancer Genome Atlas (TCGA). Despite technical differences (e.g., formalin-fixed vs. fresh-frozen tissue), the distribution of mutations and their variant classifications for major HGSC genes were nearly identical across study populations. However, de novo significantly mutated gene analysis identified genes not previously reported in the TCGA analysis, including the oncogene KRAS and the potential tumor suppressor OBSCN. The prevalence of the homologous recombination deficiency signature was higher among Black individuals with the immunoreactive gene expression subtype compared with the mesenchymal and proliferative subtypes. These findings were confirmed by comparing the data from Black patients to 123 White patients with identical tissue collection and processing. Overall, this study suggests that, while most features of HGSC tumor phenotypes are similar in Black and White populations, there may be clinically-relevant differences. If validated, these phenotypes may be important for clinical decision-making and would have been missed by characterizing tumors from White individuals only.","PeriodicalId":9441,"journal":{"name":"Cancer research","volume":"54 1","pages":""},"PeriodicalIF":11.2,"publicationDate":"2025-03-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143590163","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-03-07DOI: 10.1158/0008-5472.can-24-2227
Yu Kong, Fan Wang, Renwei Jing, Qian Zhao, Xuejiao Lv, Yingying Zhao, Ye Yuan, Xianyou Xia, Yu Sun, Yujie Tong, Han Yan, Qian Li, Ting Li, Lei Cao, Deng Liu, Dawei Huo, Shao-Kai Sun, Francisco Morís, Yujie Tang, Xudong Wu
Diffuse intrinsic pontine gliomas (DIPGs) are lethal pediatric brain tumors that frequently harbor H3K27M mutations and lack effective treatments. Here, our epigenomic analyses uncovered an enrichment of SP/KLF transcription factors in open chromatin regions specifically in H3K27M-mutated DIPG cells compared to normal pontine neural progenitor cells. SP1 depletion or inhibition of SP/KLF DNA binding with EC-8042, an optimized mithramycin analog, significantly suppressed the proliferation and invasiveness of H3K27M-DIPG cells. A screen of epigenetic drugs showed that histone deacetylase inhibitors (HDACi) synergized with EC-8042 to suppress H3K27M-DIPG cell growth. Unexpectedly, HDACi activated transcriptional programs that enhanced tumor adaptability and invasiveness, an effect counteracted by EC-8042. Mechanistically, HDACi treatment enhanced chromatin accessibility to SP/KLF factors, while EC-8042 disrupted both the primary SP/KLF transcription regulatory network and the HDACi-induced secondary network. Consequently, the combination treatment significantly impeded tumor progression in orthotopic xenograft models. Transcriptomic profiling indicated that this combinatorial strategy induced transcriptional changes associated with improved prognosis in DIPG patients. Thus, this study identifies a therapeutic approach for H3K27M-mutated DIPGs and sheds light on the limitations of HDACi in treating solid tumors.
{"title":"Targeting the SP/KLF Transcriptional Regulatory Network Synergizes with HDAC Inhibition to Impede Progression of H3K27M Diffuse Intrinsic Pontine Glioma","authors":"Yu Kong, Fan Wang, Renwei Jing, Qian Zhao, Xuejiao Lv, Yingying Zhao, Ye Yuan, Xianyou Xia, Yu Sun, Yujie Tong, Han Yan, Qian Li, Ting Li, Lei Cao, Deng Liu, Dawei Huo, Shao-Kai Sun, Francisco Morís, Yujie Tang, Xudong Wu","doi":"10.1158/0008-5472.can-24-2227","DOIUrl":"https://doi.org/10.1158/0008-5472.can-24-2227","url":null,"abstract":"Diffuse intrinsic pontine gliomas (DIPGs) are lethal pediatric brain tumors that frequently harbor H3K27M mutations and lack effective treatments. Here, our epigenomic analyses uncovered an enrichment of SP/KLF transcription factors in open chromatin regions specifically in H3K27M-mutated DIPG cells compared to normal pontine neural progenitor cells. SP1 depletion or inhibition of SP/KLF DNA binding with EC-8042, an optimized mithramycin analog, significantly suppressed the proliferation and invasiveness of H3K27M-DIPG cells. A screen of epigenetic drugs showed that histone deacetylase inhibitors (HDACi) synergized with EC-8042 to suppress H3K27M-DIPG cell growth. Unexpectedly, HDACi activated transcriptional programs that enhanced tumor adaptability and invasiveness, an effect counteracted by EC-8042. Mechanistically, HDACi treatment enhanced chromatin accessibility to SP/KLF factors, while EC-8042 disrupted both the primary SP/KLF transcription regulatory network and the HDACi-induced secondary network. Consequently, the combination treatment significantly impeded tumor progression in orthotopic xenograft models. Transcriptomic profiling indicated that this combinatorial strategy induced transcriptional changes associated with improved prognosis in DIPG patients. Thus, this study identifies a therapeutic approach for H3K27M-mutated DIPGs and sheds light on the limitations of HDACi in treating solid tumors.","PeriodicalId":9441,"journal":{"name":"Cancer research","volume":"212 1","pages":""},"PeriodicalIF":11.2,"publicationDate":"2025-03-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143575429","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Immune checkpoint blockade (ICB) therapies have achieved significant breakthroughs in cancer treatment over the past decade. However, ICB is largely ineffective in desert-type gastric cancer (GC) due to intrinsic tumor heterogeneity and a highly immunosuppressive tumor microenvironment (TME). Transforming tumors from immunosuppressive to immunostimulatory is a potential approach to enhance ICB response. Here, we developed a chromosomal instability (CIN) subtype GC mouse model with an immunoactive TME and a stem cell-originated mouse-derived allograft (MDA) model with an immunosuppressed TME to investigate mechanisms regulating the tumor immunophenotype and uncover therapeutic strategies to remodel the TME. Blocking β-catenin signaling attenuated the immunochemotherapeutic resistance of MDA tumors. The tyrosine kinase inhibitor apatinib reprogrammed the TME by increasing CD8+ T cells and IGHA+ plasma cells infiltration and decreasing M2 macrophages, but apatinib also induced PD-L1 and CD80 expression in both human and mouse desert-type tumors. Oxaliplatin decreased the apatinib-induced expression of immune checkpoints and enhanced the antitumor efficacy of immunotherapy. A prospective clinical trial (NCT04195828) demonstrated that a neoadjuvant regimen of apatinib plus ICB and chemotherapy was effective in patients with desert-type GC. Collectively, these findings identify potential drug targets for immune desert-type GC driven by β-catenin signaling.
{"title":"Combining Apatinib and Oxaliplatin Remodels the Immunosuppressive Tumor Microenvironment and Sensitizes Desert-Type Gastric Cancer to Immunotherapy","authors":"Guang-Tan Lin, Cheng Yan, Lu-Jie Li, Xiao-Wen Qiu, Yu-Xuan Zhao, Ju-Li Lin, Yu-Jing Chen, Chuan Feng, Shao-Qiong Chen, Jian-Wei Xie, Chao-Hui Zheng, Sachiyo Nomura, Chang-Ming Huang, Ping Li, Long-Long Cao","doi":"10.1158/0008-5472.can-24-2697","DOIUrl":"https://doi.org/10.1158/0008-5472.can-24-2697","url":null,"abstract":"Immune checkpoint blockade (ICB) therapies have achieved significant breakthroughs in cancer treatment over the past decade. However, ICB is largely ineffective in desert-type gastric cancer (GC) due to intrinsic tumor heterogeneity and a highly immunosuppressive tumor microenvironment (TME). Transforming tumors from immunosuppressive to immunostimulatory is a potential approach to enhance ICB response. Here, we developed a chromosomal instability (CIN) subtype GC mouse model with an immunoactive TME and a stem cell-originated mouse-derived allograft (MDA) model with an immunosuppressed TME to investigate mechanisms regulating the tumor immunophenotype and uncover therapeutic strategies to remodel the TME. Blocking β-catenin signaling attenuated the immunochemotherapeutic resistance of MDA tumors. The tyrosine kinase inhibitor apatinib reprogrammed the TME by increasing CD8+ T cells and IGHA+ plasma cells infiltration and decreasing M2 macrophages, but apatinib also induced PD-L1 and CD80 expression in both human and mouse desert-type tumors. Oxaliplatin decreased the apatinib-induced expression of immune checkpoints and enhanced the antitumor efficacy of immunotherapy. A prospective clinical trial (NCT04195828) demonstrated that a neoadjuvant regimen of apatinib plus ICB and chemotherapy was effective in patients with desert-type GC. Collectively, these findings identify potential drug targets for immune desert-type GC driven by β-catenin signaling.","PeriodicalId":9441,"journal":{"name":"Cancer research","volume":"53 1","pages":""},"PeriodicalIF":11.2,"publicationDate":"2025-03-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143575427","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-03-07DOI: 10.1158/0008-5472.can-25-0987
Hannah C. Bergo, Logan B. Leak, Trever G. Bivona
Therapy resistance is a significant cause of death in patients treated with targeted cancer therapy in diverse oncogene-driven cancers. A better understanding of resistance mechanisms can lay the foundation for improving existing and developing new therapies. A recent elegant study published in Nature Chemical Biology sheds light on a new resistance mechanism. The authors define a novel role for ARAF, a member of the RAF protein family (A-, B-, C-RAF), that is distinct from its previously understood role as a RAS effector and MEK protein kinase in the MAPK pathway. They describe how ARAF sequesters active RAS at the plasma membrane in phase-separated condensates to sustain signaling and prevent inactivation by the RAS GTPase activating protein (GAP) neurofibromin 1 (NF1). This study underscores emerging roles for biomolecular condensates in cancer and highlights important implications for disrupting protein condensates to address treatment resistance to RAS (and RAS pathway) targeted therapies. The study also illuminates evolutionary functional distinction between the RAF proteins and indicates unique biology for ARAF in normal physiology and disease.
{"title":"Condensates as a culprit in RAS activation and inhibitor resistance","authors":"Hannah C. Bergo, Logan B. Leak, Trever G. Bivona","doi":"10.1158/0008-5472.can-25-0987","DOIUrl":"https://doi.org/10.1158/0008-5472.can-25-0987","url":null,"abstract":"Therapy resistance is a significant cause of death in patients treated with targeted cancer therapy in diverse oncogene-driven cancers. A better understanding of resistance mechanisms can lay the foundation for improving existing and developing new therapies. A recent elegant study published in Nature Chemical Biology sheds light on a new resistance mechanism. The authors define a novel role for ARAF, a member of the RAF protein family (A-, B-, C-RAF), that is distinct from its previously understood role as a RAS effector and MEK protein kinase in the MAPK pathway. They describe how ARAF sequesters active RAS at the plasma membrane in phase-separated condensates to sustain signaling and prevent inactivation by the RAS GTPase activating protein (GAP) neurofibromin 1 (NF1). This study underscores emerging roles for biomolecular condensates in cancer and highlights important implications for disrupting protein condensates to address treatment resistance to RAS (and RAS pathway) targeted therapies. The study also illuminates evolutionary functional distinction between the RAF proteins and indicates unique biology for ARAF in normal physiology and disease.","PeriodicalId":9441,"journal":{"name":"Cancer research","volume":"87 1","pages":""},"PeriodicalIF":11.2,"publicationDate":"2025-03-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143575323","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-03-05DOI: 10.1158/0008-5472.can-23-3918
Kelly M. Mahuron, Osmaan Shahid, Prachi Sao, Clinton Wu, Alexandra M. Haugh, Laura A. Huppert, Lauren S. Levine, Margaret M. Lowe, Michael Alvarado, Markee Micu, Katy K. Tsai, Melissa Chow, Meromit Singer, Jason M. Schenkel, Arlene H. Sharpe, Michael D. Rosenblum, Kristen E. Pauken, Adil I. Daud
PD-1 pathway inhibitors have revolutionized cancer therapy. However, most patients do not durably benefit, highlighting the need for biomarkers to stratify patients as responders or non-responders. While CD8+ tumor infiltrating lymphocytes (TILs) have been associated with immune checkpoint therapy response, there is not a consensus on which CD8+ TIL subpopulations have the most prognostic value. Preclinical studies have focused on progenitor-like exhausted CD8+ T cells (TPEX), since TPEX proliferate more in response to PD-1 inhibitors than other exhausted T cell (TEX) subpopulations. However, immune checkpoint inhibitor (ICI) treatment drives TPEX differentiation into other TEX populations that can mediate anti-tumor immunity. These data complicate the ability to identify prognostically important T cell populations in patients that predict ICI treatment response. In this study, we found that advanced melanoma patients with ≥20% of CD8+ TILs co-expressing PD-1 and CTLA-4 (termed CPHi TILs) had better objective response rates and survival following PD-1 monotherapy than those below this threshold. Characterization of the CPHi TIL subset using bulk and single cell RNA sequencing showed that while TPEX-like cells were present within the CPHi subset, they were in the minority of these cells. Rather, the CPHi population was numerically dominated by other subsets, including cycling, terminally exhausted, cytotoxic-like, and/or resident memory-like TEX populations, and a subset enriched for glycolytic genes. Collectively, these data show that CPHi TILs correlate with response in melanoma, but this TIL subset is a heterogenous mix of different subpopulations that may differentially contribute to anti-tumor immunity following checkpoint blockade.
PD-1 通路抑制剂给癌症治疗带来了革命性的变化。然而，大多数患者并不能持久获益，这就凸显了对生物标志物的需求，以便将患者分层为应答者或无应答者。虽然 CD8+ 肿瘤浸润淋巴细胞（TILs）与免疫检查点疗法的反应有关，但对于哪些 CD8+ TIL 亚群最具预后价值尚未达成共识。临床前研究主要关注祖细胞样衰竭 CD8+ T 细胞（TPEX），因为 TPEX 对 PD-1 抑制剂的增殖反应比其他衰竭 T 细胞（TEX）亚群更强。然而，免疫检查点抑制剂（ICI）治疗可促使TPEX分化为其他TEX亚群，从而介导抗肿瘤免疫。这些数据使得在患者中识别预后重要的 T 细胞群以预测 ICI 治疗反应的能力变得更加复杂。在这项研究中，我们发现，CD8+ TILs 共表达 PD-1 和 CTLA-4 的比例≥20%（称为 CPHi TILs）的晚期黑色素瘤患者接受 PD-1 单药治疗后的客观反应率和生存率均优于低于这一阈值的患者。使用大量和单细胞RNA测序对CPHi TIL亚群进行的表征显示，虽然CPHi亚群中存在TPEX样细胞，但它们只是这些细胞中的少数。相反，CPHi 群体在数量上以其他亚群为主，包括循环、终末衰竭、细胞毒性样和/或常驻记忆样 TEX 群体，以及一个富含糖酵解基因的亚群。总之，这些数据表明，CPHi TIL 与黑色素瘤的反应相关，但这一 TIL 亚群是不同亚群的异质混合体，可能在检查点阻断后对抗肿瘤免疫做出不同的贡献。
{"title":"Single Cell Analyses Reveal a Functionally Heterogeneous Exhausted CD8+ T Cell Subpopulation that is Correlated with Response to Checkpoint Therapy in Melanoma","authors":"Kelly M. Mahuron, Osmaan Shahid, Prachi Sao, Clinton Wu, Alexandra M. Haugh, Laura A. Huppert, Lauren S. Levine, Margaret M. Lowe, Michael Alvarado, Markee Micu, Katy K. Tsai, Melissa Chow, Meromit Singer, Jason M. Schenkel, Arlene H. Sharpe, Michael D. Rosenblum, Kristen E. Pauken, Adil I. Daud","doi":"10.1158/0008-5472.can-23-3918","DOIUrl":"https://doi.org/10.1158/0008-5472.can-23-3918","url":null,"abstract":"PD-1 pathway inhibitors have revolutionized cancer therapy. However, most patients do not durably benefit, highlighting the need for biomarkers to stratify patients as responders or non-responders. While CD8+ tumor infiltrating lymphocytes (TILs) have been associated with immune checkpoint therapy response, there is not a consensus on which CD8+ TIL subpopulations have the most prognostic value. Preclinical studies have focused on progenitor-like exhausted CD8+ T cells (TPEX), since TPEX proliferate more in response to PD-1 inhibitors than other exhausted T cell (TEX) subpopulations. However, immune checkpoint inhibitor (ICI) treatment drives TPEX differentiation into other TEX populations that can mediate anti-tumor immunity. These data complicate the ability to identify prognostically important T cell populations in patients that predict ICI treatment response. In this study, we found that advanced melanoma patients with ≥20% of CD8+ TILs co-expressing PD-1 and CTLA-4 (termed CPHi TILs) had better objective response rates and survival following PD-1 monotherapy than those below this threshold. Characterization of the CPHi TIL subset using bulk and single cell RNA sequencing showed that while TPEX-like cells were present within the CPHi subset, they were in the minority of these cells. Rather, the CPHi population was numerically dominated by other subsets, including cycling, terminally exhausted, cytotoxic-like, and/or resident memory-like TEX populations, and a subset enriched for glycolytic genes. Collectively, these data show that CPHi TILs correlate with response in melanoma, but this TIL subset is a heterogenous mix of different subpopulations that may differentially contribute to anti-tumor immunity following checkpoint blockade.","PeriodicalId":9441,"journal":{"name":"Cancer research","volume":"10 2 1","pages":""},"PeriodicalIF":11.2,"publicationDate":"2025-03-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143560602","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-03-04DOI: 10.1158/0008-5472.can-24-2982
Xiao Yang, Yue Deng, Ying Ye, Jingshu Meng, Mengyao Su, Wenwen Wei, You Qin, Haibo Zhang, Yu Tian, Suke Deng, Zhiyun Liao, Zhiyuan Zhou, Jie Li, Yan Hu, Bin Zhang, Yajie Sun, Lu Wen, Zhanjie Zhang, Fang Huang, Chao Wan, Kunyu Yang
Adaptive resistance to immunotherapy remains a significant challenge in cancer treatment. The reshaping of the tumor immune microenvironment in response to therapeutic pressures is a crucial factor contributing to this resistance. Here, by comprehensive metabolic profiling of tumor tissues, we identified elevated itaconate in response to anti-PD-1 therapy as an adaptive resistance mechanism that promoted immune escape and tumor progression. CD8+ T-cell-derived interferon (IFN)-γ induced a significant upregulation of cis-aconitate decarboxylase 1 (ACOD1) in macrophages via the JAK-STAT1 pathway, thereby rewiring the Krebs cycle toward itaconate production. In murine models, macrophage-specific deletion of Acod1 increased the anti-tumor efficacy of anti-PD-1 therapy and improved survival. Additionally, itaconate and its derivative, 4-octyl itaconate (4-OI), suppressed the tumor antigen presentation and cross-priming ability of dendritic cells (DCs), resulting in the impairment of antigen-specific T-cell anti-tumor responses. In summary, these findings identify an IFN-γ-dependent immunometabolic mechanism of anti-PD-1 resistance, providing a promising strategy for combination therapy.
免疫疗法的适应性抗药性仍然是癌症治疗中的一项重大挑战。针对治疗压力重塑肿瘤免疫微环境是导致这种抗药性的关键因素。在这里，通过对肿瘤组织进行全面的代谢分析，我们确定了抗PD-1疗法引起的伊塔康酸升高是一种促进免疫逃逸和肿瘤进展的适应性耐药机制。CD8+ T细胞衍生的干扰素（IFN）-γ通过JAK-STAT1途径诱导巨噬细胞中的顺式乌头酸脱羧酶1（ACOD1）显著上调，从而重新连接了克里布循环，使其向伊塔康酸的产生方向发展。在小鼠模型中，巨噬细胞特异性缺失 Acod1 可提高抗 PD-1 疗法的抗肿瘤疗效并改善存活率。此外，伊它康酸及其衍生物伊它康酸 4-辛酯（4-OI）抑制了肿瘤抗原呈递和树突状细胞（DCs）的交叉刺激能力，导致抗原特异性 T 细胞抗肿瘤反应受损。总之，这些发现确定了抗PD-1耐药性的IFN-γ依赖性免疫代谢机制，为联合治疗提供了一种前景广阔的策略。
{"title":"Macrophage-Derived Itaconate Suppresses Dendritic Cell Function to Promote Acquired Resistance to Anti-PD-1 Immunotherapy","authors":"Xiao Yang, Yue Deng, Ying Ye, Jingshu Meng, Mengyao Su, Wenwen Wei, You Qin, Haibo Zhang, Yu Tian, Suke Deng, Zhiyun Liao, Zhiyuan Zhou, Jie Li, Yan Hu, Bin Zhang, Yajie Sun, Lu Wen, Zhanjie Zhang, Fang Huang, Chao Wan, Kunyu Yang","doi":"10.1158/0008-5472.can-24-2982","DOIUrl":"https://doi.org/10.1158/0008-5472.can-24-2982","url":null,"abstract":"Adaptive resistance to immunotherapy remains a significant challenge in cancer treatment. The reshaping of the tumor immune microenvironment in response to therapeutic pressures is a crucial factor contributing to this resistance. Here, by comprehensive metabolic profiling of tumor tissues, we identified elevated itaconate in response to anti-PD-1 therapy as an adaptive resistance mechanism that promoted immune escape and tumor progression. CD8+ T-cell-derived interferon (IFN)-γ induced a significant upregulation of cis-aconitate decarboxylase 1 (ACOD1) in macrophages via the JAK-STAT1 pathway, thereby rewiring the Krebs cycle toward itaconate production. In murine models, macrophage-specific deletion of Acod1 increased the anti-tumor efficacy of anti-PD-1 therapy and improved survival. Additionally, itaconate and its derivative, 4-octyl itaconate (4-OI), suppressed the tumor antigen presentation and cross-priming ability of dendritic cells (DCs), resulting in the impairment of antigen-specific T-cell anti-tumor responses. In summary, these findings identify an IFN-γ-dependent immunometabolic mechanism of anti-PD-1 resistance, providing a promising strategy for combination therapy.","PeriodicalId":9441,"journal":{"name":"Cancer research","volume":"16 1","pages":""},"PeriodicalIF":11.2,"publicationDate":"2025-03-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143546148","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-03-04DOI: 10.1158/0008-5472.can-24-3196
Meixi Wang, Fangdi Zou, Shengxin Wang, Yichen Yang, Cong Xia, Lu Chen, Ben Liu, Lian Li, Mulin Jun Li, Haixin Li, Weijie Song, Ruifang Niu, Zhiyong Yuan, Jie Yang, Xiangchun Li, Kexin Chen, Zhiqiang Wu, Zeyun Mi
As the third most common cause of cancer-related mortality, hepatocellular carcinoma (HCC) is a global health concern. Despite its prevalence, treatment options are limited, underscoring the need to identify potential therapeutic targets and strategies. Here, we identified amplification of CRTC2, situated in the 1q21.3 region, due to copy number alterations in HCC. In a cohort of patients with HCC, CRTC2 protein levels were frequently elevated and correlated with poor prognosis. Genetic deletion of CRTC2 significantly impeded the onset and progression of HCC in mouse models. CRTC2 formed cytoplasmic condensates that recruited the m6A reader YTHDF2. Furthermore, CRTC2 promoted the translocation of m6A-modified mRNAs from decay sites to polyribosomes by interacting with PABP1. The activities of CRTC2 counteracted YTHDF2-mediated mRNA degradation to enhance the translational efficiency of specific mRNAs, including those encoding LRP5 and c-Jun. Targeting CRTC2 in hepatocytes using AAV8.sgCRTC2 elicited substantial therapeutic benefits in HCC mouse model and significantly enhanced the sensitivity to lenvatinib. Together, this research elucidates the pivotal role and underlying molecular mechanisms of CRTC2 in hepatocarcinogenesis and lenvatinib-resistance, highlighting its potential clinical and therapeutic applications.
{"title":"CRTC2 Forms Co-condensates with YTHDF2 that Enhance Translational Efficiency of m6A-Modified mRNAs to Drive Hepatocarcinogenesis and Lenvatinib Resistance","authors":"Meixi Wang, Fangdi Zou, Shengxin Wang, Yichen Yang, Cong Xia, Lu Chen, Ben Liu, Lian Li, Mulin Jun Li, Haixin Li, Weijie Song, Ruifang Niu, Zhiyong Yuan, Jie Yang, Xiangchun Li, Kexin Chen, Zhiqiang Wu, Zeyun Mi","doi":"10.1158/0008-5472.can-24-3196","DOIUrl":"https://doi.org/10.1158/0008-5472.can-24-3196","url":null,"abstract":"As the third most common cause of cancer-related mortality, hepatocellular carcinoma (HCC) is a global health concern. Despite its prevalence, treatment options are limited, underscoring the need to identify potential therapeutic targets and strategies. Here, we identified amplification of CRTC2, situated in the 1q21.3 region, due to copy number alterations in HCC. In a cohort of patients with HCC, CRTC2 protein levels were frequently elevated and correlated with poor prognosis. Genetic deletion of CRTC2 significantly impeded the onset and progression of HCC in mouse models. CRTC2 formed cytoplasmic condensates that recruited the m6A reader YTHDF2. Furthermore, CRTC2 promoted the translocation of m6A-modified mRNAs from decay sites to polyribosomes by interacting with PABP1. The activities of CRTC2 counteracted YTHDF2-mediated mRNA degradation to enhance the translational efficiency of specific mRNAs, including those encoding LRP5 and c-Jun. Targeting CRTC2 in hepatocytes using AAV8.sgCRTC2 elicited substantial therapeutic benefits in HCC mouse model and significantly enhanced the sensitivity to lenvatinib. Together, this research elucidates the pivotal role and underlying molecular mechanisms of CRTC2 in hepatocarcinogenesis and lenvatinib-resistance, highlighting its potential clinical and therapeutic applications.","PeriodicalId":9441,"journal":{"name":"Cancer research","volume":"32 1","pages":""},"PeriodicalIF":11.2,"publicationDate":"2025-03-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143546205","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-03-04DOI: 10.1158/0008-5472.can-24-2219
Tareq Saleh, Edward F. Greenberg, Anthony C. Faber, Hisashi Harada, David A. Gewirtz
Cancer chemotherapy and radiotherapy are rarely successful in eliminating the entire tumor population, often leaving behind a subpopulation of senescent cells that can contribute to disease recurrence. These senescent tumor cells also secrete various chemokines and cytokines that may be tumor-promoting and immunosuppressive. Recognition of the deleterious impact of therapy-induced senescence has led to the preclinical development of senolytic compounds that eliminate senescent cells, representing a potential strategy to enhance the efficacy of conventional and targeted anticancer therapy. However, it remains uncertain whether this strategy can or will be translated to the clinic. This review provides a summary of the recent preclinical literature supporting the use of senolytics as an adjunct for cancer treatment, discusses the limitations associated with current preclinical models, and provides perspectives on the clinical development of senolytics in cancer treatment regimens. Overall, preclinical studies support the potential of senolytics to enhance efficacy and prolong the antitumor activity of current standard-of-care cancer therapies that promote senescence. However, further work is needed to develop optimal senolytic agents with the appropriate combination of properties for clinical testing, specifically activity in the context of therapy-induced senescence with acceptable tolerability.
{"title":"A Critical Appraisal of the Utility of Targeting Therapy-induced Senescence for Cancer Treatment","authors":"Tareq Saleh, Edward F. Greenberg, Anthony C. Faber, Hisashi Harada, David A. Gewirtz","doi":"10.1158/0008-5472.can-24-2219","DOIUrl":"https://doi.org/10.1158/0008-5472.can-24-2219","url":null,"abstract":"Cancer chemotherapy and radiotherapy are rarely successful in eliminating the entire tumor population, often leaving behind a subpopulation of senescent cells that can contribute to disease recurrence. These senescent tumor cells also secrete various chemokines and cytokines that may be tumor-promoting and immunosuppressive. Recognition of the deleterious impact of therapy-induced senescence has led to the preclinical development of senolytic compounds that eliminate senescent cells, representing a potential strategy to enhance the efficacy of conventional and targeted anticancer therapy. However, it remains uncertain whether this strategy can or will be translated to the clinic. This review provides a summary of the recent preclinical literature supporting the use of senolytics as an adjunct for cancer treatment, discusses the limitations associated with current preclinical models, and provides perspectives on the clinical development of senolytics in cancer treatment regimens. Overall, preclinical studies support the potential of senolytics to enhance efficacy and prolong the antitumor activity of current standard-of-care cancer therapies that promote senescence. However, further work is needed to develop optimal senolytic agents with the appropriate combination of properties for clinical testing, specifically activity in the context of therapy-induced senescence with acceptable tolerability.","PeriodicalId":9441,"journal":{"name":"Cancer research","volume":"70 1","pages":""},"PeriodicalIF":11.2,"publicationDate":"2025-03-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143546149","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
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