Pub Date : 2024-10-03DOI: 10.1007/s00262-024-03768-5
Diana Tronik-Le Roux, Marina Daouya, Isabelle Poras, François Desgrandchamps, Edgardo D Carosella
The development of immunotherapies has proved to be clinically encouraging to re-establish the immune function modified by the expression of immune inhibitory molecules in tumors. However, there are still patients with poor survival rates following treatment. The elucidation of molecular mechanisms triggered by the neo-expression of particular IC in tumors would constitute a major step toward better understanding tumor evolution and would help to design future clinical protocols. To this end, we investigate the modifications triggered by the neo-expression of the immune checkpoints HLA-G in ccRCC tumor cells. We demonstrate, for the first time, that HLA-G modifies key genes implicated mainly in tumor development, angiogenesis, calcium flow and mitochondria dynamics. The involvement of HLA-G on the expression of genes belonging to these pathways such as ADAM-12, NCAM1 and NRP1 was confirmed by the CRISPR/Cas9-mediated edition of HLA-G. The data reveal multifaceted roles of HLA-G in tumor cells which are far beyond the well-known function of HLA-G in the immune anti-tumor response. This warrants further investigation of HLA-G and these new partners in tumors of different origin so as to propose future new treatments to improve health patient's outcome.
{"title":"HLA-G neo-expression modifies genetic programs governing tumor cell lines.","authors":"Diana Tronik-Le Roux, Marina Daouya, Isabelle Poras, François Desgrandchamps, Edgardo D Carosella","doi":"10.1007/s00262-024-03768-5","DOIUrl":"10.1007/s00262-024-03768-5","url":null,"abstract":"<p><p>The development of immunotherapies has proved to be clinically encouraging to re-establish the immune function modified by the expression of immune inhibitory molecules in tumors. However, there are still patients with poor survival rates following treatment. The elucidation of molecular mechanisms triggered by the neo-expression of particular IC in tumors would constitute a major step toward better understanding tumor evolution and would help to design future clinical protocols. To this end, we investigate the modifications triggered by the neo-expression of the immune checkpoints HLA-G in ccRCC tumor cells. We demonstrate, for the first time, that HLA-G modifies key genes implicated mainly in tumor development, angiogenesis, calcium flow and mitochondria dynamics. The involvement of HLA-G on the expression of genes belonging to these pathways such as ADAM-12, NCAM1 and NRP1 was confirmed by the CRISPR/Cas9-mediated edition of HLA-G. The data reveal multifaceted roles of HLA-G in tumor cells which are far beyond the well-known function of HLA-G in the immune anti-tumor response. This warrants further investigation of HLA-G and these new partners in tumors of different origin so as to propose future new treatments to improve health patient's outcome.</p>","PeriodicalId":9595,"journal":{"name":"Cancer Immunology, Immunotherapy","volume":"73 12","pages":"247"},"PeriodicalIF":5.4,"publicationDate":"2024-10-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11447172/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142364451","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Extramammary Paget's disease (EMPD) is a rare cutaneous malignancy characterized by its uncertain etiology and metastatic potential. Surgery remains the first-line clinical treatment for EMPD, but the efficacy of radiotherapy and chemotherapy remains to be fully evaluated, and new therapies for EMPD are urgently needed. In this study, we initially screened 815 EMPD patients in the Surveillance, Epidemiology, and End Results (SEER) database and analyzed their clinical features and prognostic factors. Using the dataset from the Genome Sequence Archive (GSA) database, we subsequently conducted weighted gene coexpression network analysis (WGCNA), gene set enrichment analysis (GSEA), gene set variation analysis (GSVA), and immune infiltration analyses, grouping the samples based on EMPD disease status and the levels of ERBB2 expression. The prognostic analysis based on the SEER database identified increased age at diagnosis, distant metastasis, and receipt of radiotherapy as independent risk factors for EMPD. Moreover, our results indicated that patients who received chemotherapy had worse prognoses than those who did not, highlighting the urgent need for novel treatment approaches for EMPD. Functional analysis of the GSA-derived dataset revealed that EMPD tissues were significantly enriched in immune-related pathways compared with normal skin tissues. Compared with those with high ERBB2 expression, tissues with low ERBB2 expression displayed greater immunogenicity and enrichment of immune pathways, particularly those related to B cells. These findings suggest that patients with low ERBB2 expression are likely to benefit from immunotherapy, especially B-cell-related immunotherapy.
{"title":"Immunotherapy may be more appropriate for ERBB2 low-expressing extramammary paget's disease patients: a prognosis analysis and exploration of targeted therapy and immunotherapy of extramammary paget's disease patients.","authors":"Jiawen Yang, Yurong Chen, Xiuyuan Zhang, Ziyan Tong, Shanshan Weng, Ning Zhu, Ying Yuan","doi":"10.1007/s00262-024-03846-8","DOIUrl":"10.1007/s00262-024-03846-8","url":null,"abstract":"<p><p>Extramammary Paget's disease (EMPD) is a rare cutaneous malignancy characterized by its uncertain etiology and metastatic potential. Surgery remains the first-line clinical treatment for EMPD, but the efficacy of radiotherapy and chemotherapy remains to be fully evaluated, and new therapies for EMPD are urgently needed. In this study, we initially screened 815 EMPD patients in the Surveillance, Epidemiology, and End Results (SEER) database and analyzed their clinical features and prognostic factors. Using the dataset from the Genome Sequence Archive (GSA) database, we subsequently conducted weighted gene coexpression network analysis (WGCNA), gene set enrichment analysis (GSEA), gene set variation analysis (GSVA), and immune infiltration analyses, grouping the samples based on EMPD disease status and the levels of ERBB2 expression. The prognostic analysis based on the SEER database identified increased age at diagnosis, distant metastasis, and receipt of radiotherapy as independent risk factors for EMPD. Moreover, our results indicated that patients who received chemotherapy had worse prognoses than those who did not, highlighting the urgent need for novel treatment approaches for EMPD. Functional analysis of the GSA-derived dataset revealed that EMPD tissues were significantly enriched in immune-related pathways compared with normal skin tissues. Compared with those with high ERBB2 expression, tissues with low ERBB2 expression displayed greater immunogenicity and enrichment of immune pathways, particularly those related to B cells. These findings suggest that patients with low ERBB2 expression are likely to benefit from immunotherapy, especially B-cell-related immunotherapy.</p>","PeriodicalId":9595,"journal":{"name":"Cancer Immunology, Immunotherapy","volume":"73 12","pages":"252"},"PeriodicalIF":5.4,"publicationDate":"2024-10-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11447174/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142364452","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-10-03DOI: 10.1007/s00262-024-03833-z
Xiaoyu Sun, Yaoqi Gui, Tai Yang, Lingbing Chen, Yi Zhang, Ling Yan, Weixian Chen, Bo Wang
Background: Since differentiating malignant ascites from benign ascites has always been a clinical difficult, recognition of novel biomarkers in malignant ascites of hepatocellular carcinoma (HCC) patients could be helpful for establishing a diagnosis for HCC patients with ascitic fluids.
Methods: Thirty-five HCC patients with malignant ascites and chronic liver diseases patients with benign ascites were enrolled. Serum and ascites specimens were collected to determine TAN subpopulations and NETs concentration. Then, the correlation between ascitic NETs levels and clinical features were analyzed, and ROC curves were generated to evaluate the diagnostic value of NETs. For in vitro study, fresh neutrophils were employed to explore the underlying mechanism of TAN polarization and NETs formation using RNAseq analysis.
Results: Significantly increased pro-tumor PD-L1+ TANs and higher lactate levels were measured in HCC ascites. RNAseq data showed that lactate regulated genes expression involving PD-L1 expression and NETs formation, suggesting that ascitic lactate might be responsible for tumor progression in TME. Then, NETs-related markers including calprotectin, dsDNA, CitH3, MPO and MPO-DNA were found dramatically elevated in malignant ascites. Next, correlation analysis revealed that ascitic NETs levels positively correlated with LDH, a classic ascitic biochemical indicator. Furthermore, we identified the diagnostic values of NETs in discriminating malignant ascites from benign ascites.
Conclusions: Our findings highlighted that elevated ascitic NETs served as a biomarker in HCC patients with malignant ascites, which provided useful insights for both clinical and basic research for malignant ascites diagnosis and management.
{"title":"PD-L1<sup>+</sup> neutrophils induced NETs in malignant ascites is a potential biomarker in HCC.","authors":"Xiaoyu Sun, Yaoqi Gui, Tai Yang, Lingbing Chen, Yi Zhang, Ling Yan, Weixian Chen, Bo Wang","doi":"10.1007/s00262-024-03833-z","DOIUrl":"10.1007/s00262-024-03833-z","url":null,"abstract":"<p><strong>Background: </strong>Since differentiating malignant ascites from benign ascites has always been a clinical difficult, recognition of novel biomarkers in malignant ascites of hepatocellular carcinoma (HCC) patients could be helpful for establishing a diagnosis for HCC patients with ascitic fluids.</p><p><strong>Methods: </strong>Thirty-five HCC patients with malignant ascites and chronic liver diseases patients with benign ascites were enrolled. Serum and ascites specimens were collected to determine TAN subpopulations and NETs concentration. Then, the correlation between ascitic NETs levels and clinical features were analyzed, and ROC curves were generated to evaluate the diagnostic value of NETs. For in vitro study, fresh neutrophils were employed to explore the underlying mechanism of TAN polarization and NETs formation using RNAseq analysis.</p><p><strong>Results: </strong>Significantly increased pro-tumor PD-L1<sup>+</sup> TANs and higher lactate levels were measured in HCC ascites. RNAseq data showed that lactate regulated genes expression involving PD-L1 expression and NETs formation, suggesting that ascitic lactate might be responsible for tumor progression in TME. Then, NETs-related markers including calprotectin, dsDNA, CitH3, MPO and MPO-DNA were found dramatically elevated in malignant ascites. Next, correlation analysis revealed that ascitic NETs levels positively correlated with LDH, a classic ascitic biochemical indicator. Furthermore, we identified the diagnostic values of NETs in discriminating malignant ascites from benign ascites.</p><p><strong>Conclusions: </strong>Our findings highlighted that elevated ascitic NETs served as a biomarker in HCC patients with malignant ascites, which provided useful insights for both clinical and basic research for malignant ascites diagnosis and management.</p>","PeriodicalId":9595,"journal":{"name":"Cancer Immunology, Immunotherapy","volume":"73 12","pages":"254"},"PeriodicalIF":5.4,"publicationDate":"2024-10-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11447185/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142364524","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-09-17DOI: 10.1007/s00262-024-03811-5
Ruizhi Zhang, Gan Mao, Yu Tang, Chong Li, Yisong Gao, Wenxiang Nie, Tianyu Song, Suao Liu, Peng Zhang, Kaixiong Tao, Wei Li
{"title":"Correction to: Inhibition of glycolysis enhances the efficacy of immunotherapy via PDK‑mediated upregulation of PD‑L1.","authors":"Ruizhi Zhang, Gan Mao, Yu Tang, Chong Li, Yisong Gao, Wenxiang Nie, Tianyu Song, Suao Liu, Peng Zhang, Kaixiong Tao, Wei Li","doi":"10.1007/s00262-024-03811-5","DOIUrl":"10.1007/s00262-024-03811-5","url":null,"abstract":"","PeriodicalId":9595,"journal":{"name":"Cancer Immunology, Immunotherapy","volume":"73 11","pages":"236"},"PeriodicalIF":4.6,"publicationDate":"2024-09-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11408429/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142280665","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-09-13DOI: 10.1007/s00262-024-03834-y
Ruxuan Chen, Yujie Shi, Nan Fang, Chi Shao, Hui Huang, Ruili Pan, Yan Xu, Mengqi Wang, Xiangning Liu, Kai Xu, Rui Zhu, Mengzhao Wang
Background
Checkpoint inhibitor pneumonitis (CIP) is a relatively uncommon but potentially life-threatening immune-related adverse event (irAE). Lung biopsies have not been commonly performed for CIP patients. Bronchoalveolar lavage fluid (BALF) analysis is a useful diagnostic approach for interstitial lung disease. However, BALF features were inconsistent across different studies.
Methods
We retrospectively reviewed the medical records of 154 patients with pathologically confirmed malignancies and suffering from CIPs between July 2018 and December 2022. Patients who had bronchoalveolar lavage (BAL) data available were enrolled in our study. Patient clinical, laboratory, radiological and follow-up data were reviewed and analyzed.
Results
The BALF differential cell count and lymphocyte subset analysis were performed for 42 CIP patients. There were 32 males (76.2%). The mean age at diagnosis of CIP was 62.0 ± 10.4 (range: 31–78) years. The median time to onset of CIP was 98.5 days after the start of immunotherapy. There were 18 patients (42.9%) with low-grade CIPs and 24 patients (57.1%) with high-grade CIPs. The mean lymphocyte percentage was 36.7 ± 22.5%. There were 34 (81%) CIP patients with a lymphocytic cellular pattern. The median ratio of CD3+CD4+/CD3+CD8+ lymphocytes was 0.5 (0.3, 1.0). The ratio was less than 1.0 for 31 CIP patients (73.8%). However, there was no significant difference in the BALF features between patients with low-grade CIPs and those with high-grade CIPs.
Conclusions
The CD3+CD8+ lymphocytosis pattern was the main inflammatory profile in the BALF of CIP patients in this cohort. Targeting CD3+CD8+ lymphocytes might be a treatment option for CIPs.
{"title":"Bronchoalveolar lavage fluid analysis in patients with checkpoint inhibitor pneumonitis","authors":"Ruxuan Chen, Yujie Shi, Nan Fang, Chi Shao, Hui Huang, Ruili Pan, Yan Xu, Mengqi Wang, Xiangning Liu, Kai Xu, Rui Zhu, Mengzhao Wang","doi":"10.1007/s00262-024-03834-y","DOIUrl":"https://doi.org/10.1007/s00262-024-03834-y","url":null,"abstract":"<h3 data-test=\"abstract-sub-heading\">Background</h3><p>Checkpoint inhibitor pneumonitis (CIP) is a relatively uncommon but potentially life-threatening immune-related adverse event (irAE). Lung biopsies have not been commonly performed for CIP patients. Bronchoalveolar lavage fluid (BALF) analysis is a useful diagnostic approach for interstitial lung disease. However, BALF features were inconsistent across different studies.</p><h3 data-test=\"abstract-sub-heading\">Methods</h3><p>We retrospectively reviewed the medical records of 154 patients with pathologically confirmed malignancies and suffering from CIPs between July 2018 and December 2022. Patients who had bronchoalveolar lavage (BAL) data available were enrolled in our study. Patient clinical, laboratory, radiological and follow-up data were reviewed and analyzed.</p><h3 data-test=\"abstract-sub-heading\">Results</h3><p>The BALF differential cell count and lymphocyte subset analysis were performed for 42 CIP patients. There were 32 males (76.2%). The mean age at diagnosis of CIP was 62.0 ± 10.4 (range: 31–78) years. The median time to onset of CIP was 98.5 days after the start of immunotherapy. There were 18 patients (42.9%) with low-grade CIPs and 24 patients (57.1%) with high-grade CIPs. The mean lymphocyte percentage was 36.7 ± 22.5%. There were 34 (81%) CIP patients with a lymphocytic cellular pattern. The median ratio of CD3<sup>+</sup>CD4<sup>+</sup>/CD3<sup>+</sup>CD8<sup>+</sup> lymphocytes was 0.5 (0.3, 1.0). The ratio was less than 1.0 for 31 CIP patients (73.8%). However, there was no significant difference in the BALF features between patients with low-grade CIPs and those with high-grade CIPs.</p><h3 data-test=\"abstract-sub-heading\">Conclusions</h3><p>The CD3<sup>+</sup>CD8<sup>+</sup> lymphocytosis pattern was the main inflammatory profile in the BALF of CIP patients in this cohort. Targeting CD3<sup>+</sup>CD8<sup>+</sup> lymphocytes might be a treatment option for CIPs.</p>","PeriodicalId":9595,"journal":{"name":"Cancer Immunology, Immunotherapy","volume":"7 1","pages":""},"PeriodicalIF":5.8,"publicationDate":"2024-09-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142263424","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-09-13DOI: 10.1007/s00262-024-03820-4
Jiao Xu, Bixin Yu, Fan Wang, Jin Yang
Gastric cancer (GC) is a highly heterogeneous disease with a complex tumor microenvironment (TME) that encompasses multiple cell types including cancer cells, immune cells, stromal cells, and so on. Cancer-associated cells could remodel the TME and influence the progression of GC and therapeutic response. Single-cell RNA sequencing (scRNA-seq), as an emerging technology, has provided unprecedented insights into the complicated biological composition and characteristics of TME at the molecular, cellular, and immunological resolutions, offering a new idea for GC studies. In this review, we discuss the novel findings from scRNA-seq datasets revealing the origin and evolution of GC, and scRNA-seq is a powerful tool for investigating transcriptional dynamics and intratumor heterogeneity (ITH) in GC. Meanwhile, we demonstrate that the vital immune cells within TME, including T cells, B cells, macrophages, and stromal cells, play an important role in the disease progression. Additionally, we also overview that how scRNA-seq facilitates our understanding about the effects on individualized therapy of GC patients. Spatial transcriptomes (ST) have been designed to determine spatial distribution and capture local intercellular communication networks, enabling a further understanding of the relationship between the spatial background of a particular cell and its functions. In summary, scRNA-seq and other single-cell technologies provide a valuable perspective for molecular and pathological disease characteristics and hold promise for advancing basic research and clinical practice in GC.
{"title":"Single-cell RNA sequencing to map tumor heterogeneity in gastric carcinogenesis paving roads to individualized therapy","authors":"Jiao Xu, Bixin Yu, Fan Wang, Jin Yang","doi":"10.1007/s00262-024-03820-4","DOIUrl":"https://doi.org/10.1007/s00262-024-03820-4","url":null,"abstract":"<p>Gastric cancer (GC) is a highly heterogeneous disease with a complex tumor microenvironment (TME) that encompasses multiple cell types including cancer cells, immune cells, stromal cells, and so on. Cancer-associated cells could remodel the TME and influence the progression of GC and therapeutic response. Single-cell RNA sequencing (scRNA-seq), as an emerging technology, has provided unprecedented insights into the complicated biological composition and characteristics of TME at the molecular, cellular, and immunological resolutions, offering a new idea for GC studies. In this review, we discuss the novel findings from scRNA-seq datasets revealing the origin and evolution of GC, and scRNA-seq is a powerful tool for investigating transcriptional dynamics and intratumor heterogeneity (ITH) in GC. Meanwhile, we demonstrate that the vital immune cells within TME, including T cells, B cells, macrophages, and stromal cells, play an important role in the disease progression. Additionally, we also overview that how scRNA-seq facilitates our understanding about the effects on individualized therapy of GC patients. Spatial transcriptomes (ST) have been designed to determine spatial distribution and capture local intercellular communication networks, enabling a further understanding of the relationship between the spatial background of a particular cell and its functions. In summary, scRNA-seq and other single-cell technologies provide a valuable perspective for molecular and pathological disease characteristics and hold promise for advancing basic research and clinical practice in GC.</p>","PeriodicalId":9595,"journal":{"name":"Cancer Immunology, Immunotherapy","volume":"10 1","pages":""},"PeriodicalIF":5.8,"publicationDate":"2024-09-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142269401","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-09-13DOI: 10.1007/s00262-024-03825-z
Jyoti Malhotra, Subhajyoti De, Kim Nguyen, Percy Lee, Victoria Villaflor
The clinical response to immune checkpoint inhibitors may vary by tumor type and many tumors present with either primary or acquired resistance to immunotherapy. Improved understanding of the molecular and immunologic mechanisms underlying immunotherapy resistance is essential for developing biomarkers and for guiding the optimum approach to selecting treatment regimens and sequencing. This is increasingly important for tumors with primary resistance as effective biomarkers in this setting can guide clinicians about appropriate treatment regimen selection in the first-line setting. Multiple potential biological mechanisms of primary resistance have been proposed but most are yet to be validated in prospective clinical cohorts. Individual biomarkers have poor specificity and sensitivity, and the development of validated and integrated predictive models may guide which patient will benefit from monotherapy versus combination therapy. In this review, we discuss the emerging data identifying the molecular mechanisms of primary resistance to immunotherapy and explore potential therapeutic strategies to target these.
{"title":"Genomic and molecular alterations associated with primary resistance to immune checkpoint inhibitors","authors":"Jyoti Malhotra, Subhajyoti De, Kim Nguyen, Percy Lee, Victoria Villaflor","doi":"10.1007/s00262-024-03825-z","DOIUrl":"https://doi.org/10.1007/s00262-024-03825-z","url":null,"abstract":"<p>The clinical response to immune checkpoint inhibitors may vary by tumor type and many tumors present with either primary or acquired resistance to immunotherapy. Improved understanding of the molecular and immunologic mechanisms underlying immunotherapy resistance is essential for developing biomarkers and for guiding the optimum approach to selecting treatment regimens and sequencing. This is increasingly important for tumors with primary resistance as effective biomarkers in this setting can guide clinicians about appropriate treatment regimen selection in the first-line setting. Multiple potential biological mechanisms of primary resistance have been proposed but most are yet to be validated in prospective clinical cohorts. Individual biomarkers have poor specificity and sensitivity, and the development of validated and integrated predictive models may guide which patient will benefit from monotherapy versus combination therapy. In this review, we discuss the emerging data identifying the molecular mechanisms of primary resistance to immunotherapy and explore potential therapeutic strategies to target these.</p>","PeriodicalId":9595,"journal":{"name":"Cancer Immunology, Immunotherapy","volume":"23 1","pages":""},"PeriodicalIF":5.8,"publicationDate":"2024-09-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142263425","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-09-12DOI: 10.1007/s00262-024-03793-4
Satoko Matsueda, Lei Chen, Hongmei Li, Hui Yao, Fuli Yu
Tumor-infiltrating lymphocyte (TIL) therapy represents a groundbreaking advancement in the solid cancer treatment, offering new hope to patients and their families with high response rates and long overall survival. TIL therapy involves extracting immune cells from a patient's tumor tissue, expanding them ex vivo, and infusing them back into the patient to target and eliminate cancer cells. This revolutionary approach harnesses the power of the immune system to combat cancers, ushering in a new era of T cell-based therapies along with CAR-T and TCR-therapies. In this comprehensive review, we aim to elucidate the remarkable potential of TIL therapy by delving into recent advancements in basic and clinical researches. We highlight on the evolving landscape of TIL therapy as a prominent immunotherapeutic strategy, its multifaceted applications, and the promising outcomes. Additionally, we explore the future horizons of TIL therapy, next-generation TILs, and combination therapy, to overcome the limitations and improve clinical efficacy of TIL therapy.
肿瘤浸润淋巴细胞(TIL)疗法是实体瘤治疗领域的突破性进展,它为患者及其家属带来了新的希望,因为这种疗法的反应率高、总生存期长。TIL 疗法包括从患者的肿瘤组织中提取免疫细胞,将其体外扩增,然后将其回输到患者体内,以靶向消除癌细胞。这种革命性的方法利用免疫系统的力量来对抗癌症,与 CAR-T 和 TCR 疗法一起开创了基于 T 细胞疗法的新时代。在这篇综述中,我们将深入探讨基础和临床研究的最新进展,旨在阐明 TIL 疗法的巨大潜力。我们重点介绍了 TIL 疗法作为一种重要的免疫治疗策略不断发展的情况、其多方面的应用以及充满希望的成果。此外,我们还探讨了 TIL 疗法、下一代 TILs 和联合疗法的未来前景,以克服 TIL 疗法的局限性并提高其临床疗效。
{"title":"Recent clinical researches and technological development in TIL therapy","authors":"Satoko Matsueda, Lei Chen, Hongmei Li, Hui Yao, Fuli Yu","doi":"10.1007/s00262-024-03793-4","DOIUrl":"https://doi.org/10.1007/s00262-024-03793-4","url":null,"abstract":"<p>Tumor-infiltrating lymphocyte (TIL) therapy represents a groundbreaking advancement in the solid cancer treatment, offering new hope to patients and their families with high response rates and long overall survival. TIL therapy involves extracting immune cells from a patient's tumor tissue, expanding them ex vivo, and infusing them back into the patient to target and eliminate cancer cells. This revolutionary approach harnesses the power of the immune system to combat cancers, ushering in a new era of T cell-based therapies along with CAR-T and TCR-therapies. In this comprehensive review, we aim to elucidate the remarkable potential of TIL therapy by delving into recent advancements in basic and clinical researches. We highlight on the evolving landscape of TIL therapy as a prominent immunotherapeutic strategy, its multifaceted applications, and the promising outcomes. Additionally, we explore the future horizons of TIL therapy, next-generation TILs, and combination therapy, to overcome the limitations and improve clinical efficacy of TIL therapy.</p>","PeriodicalId":9595,"journal":{"name":"Cancer Immunology, Immunotherapy","volume":"7 1","pages":""},"PeriodicalIF":5.8,"publicationDate":"2024-09-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142222614","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-09-11DOI: 10.1007/s00262-024-03827-x
Keunpyo Lim, San Ha Han, Sein Han, Ji Yoon Lee, Hong Seo Choi, Dongho Choi, Chun Jeih Ryu
CD98, also known as SLC3A2, is a multifunctional cell surface molecule consisting of amino acid transporters. CD98 is ubiquitously expressed in many types of tissues, but expressed at higher levels in cancerous tissues than in normal tissues. CD98 is also upregulated in most hepatocellular carcinoma (HCC) patients; however, the function of CD98 in HCC cells has been little studied. In this study, we generated a panel of monoclonal antibodies (MAbs) against surface proteins on human embryonic stem cells (hESCs). NPB15, one of the MAbs, bound to hESCs and various cancer cells, including HCC cells and non-small cell lung carcinoma (NSCLC) cells, but not to peripheral blood mononuclear cells (PBMCs) and primary hepatocytes. Immunoprecipitation and mass spectrometry identified the target antigen of NPB15 as CD98. CD98 depletion decreased cell proliferation, clonogenic survival, and migration and induced apoptosis in HCC cells. In addition, CD98 depletion decreased the expression of cancer stem cell (CSC) markers in HCC cells. In tumorsphere cultures, the expression of CD98 interacting with NPB15 was significantly increased, as were known CSC markers. After cell sorting by NPB15, cells with high expression of CD98 (CD98-high) showed higher clonogenic survival than cells with low expression of CD98 (CD98-low) in HCC cells, suggesting CD98 as a potential CSC marker on HCC cells. The chimeric version of NPB15 was able to induce antibody-dependent cellular cytotoxicity (ADCC) against HCC cells in vitro. NPB15 injection showed antitumor activity in an HCC xenograft mouse model. The results suggest that NPB15 may be developed as a therapeutic antibody for HCC patients.
{"title":"A monoclonal antibody recognizing CD98 on human embryonic stem cells shows anti-tumor activity in hepatocellular carcinoma xenografts","authors":"Keunpyo Lim, San Ha Han, Sein Han, Ji Yoon Lee, Hong Seo Choi, Dongho Choi, Chun Jeih Ryu","doi":"10.1007/s00262-024-03827-x","DOIUrl":"https://doi.org/10.1007/s00262-024-03827-x","url":null,"abstract":"<p>CD98, also known as SLC3A2, is a multifunctional cell surface molecule consisting of amino acid transporters. CD98 is ubiquitously expressed in many types of tissues, but expressed at higher levels in cancerous tissues than in normal tissues. CD98 is also upregulated in most hepatocellular carcinoma (HCC) patients; however, the function of CD98 in HCC cells has been little studied. In this study, we generated a panel of monoclonal antibodies (MAbs) against surface proteins on human embryonic stem cells (hESCs). NPB15, one of the MAbs, bound to hESCs and various cancer cells, including HCC cells and non-small cell lung carcinoma (NSCLC) cells, but not to peripheral blood mononuclear cells (PBMCs) and primary hepatocytes. Immunoprecipitation and mass spectrometry identified the target antigen of NPB15 as CD98. CD98 depletion decreased cell proliferation, clonogenic survival, and migration and induced apoptosis in HCC cells. In addition, CD98 depletion decreased the expression of cancer stem cell (CSC) markers in HCC cells. In tumorsphere cultures, the expression of CD98 interacting with NPB15 was significantly increased, as were known CSC markers. After cell sorting by NPB15, cells with high expression of CD98 (CD98-high) showed higher clonogenic survival than cells with low expression of CD98 (CD98-low) in HCC cells, suggesting CD98 as a potential CSC marker on HCC cells. The chimeric version of NPB15 was able to induce antibody-dependent cellular cytotoxicity (ADCC) against HCC cells in vitro. NPB15 injection showed antitumor activity in an HCC xenograft mouse model. The results suggest that NPB15 may be developed as a therapeutic antibody for HCC patients.</p>","PeriodicalId":9595,"journal":{"name":"Cancer Immunology, Immunotherapy","volume":"6 1","pages":""},"PeriodicalIF":5.8,"publicationDate":"2024-09-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142222613","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Background: Immune checkpoint inhibitors (ICIs) are rarely used to treat advanced pancreatic ductal adenocarcinoma (PDAC) due to marginal efficacy.
Patients and methods: This study included 92 consecutive patients diagnosed with advanced or recurrent PDAC who received nivolumab-based treatment. Univariate and multivariate analyses were used to identify prognostic factors. A control group of 301 patients with PDAC who achieved disease control with palliative chemotherapy but without ICIs was selected for comparison using propensity score matching (PSM).
Results: The median overall survival (OS) since nivolumab treatment was 15.8 (95% confidence interval [CI], 12.5-19.0), 2.4 (95% CI 1.2-3.6), and 1.1 (95% CI 1.0-1.2) months in patients who received add-on nivolumab after achieving disease control with chemotherapy, in those who received concomitant nivolumab and chemotherapy without prerequisite confirmation of disease control, and in those who received nivolumab without concomitant chemotherapy, respectively (P < 0.001). After PSM, the median overall survival (OS) since initiation of the concomitant chemotherapy that achieved disease control was significantly longer (P = 0.026) in patients who received add-on nivolumab (19.8 months; 95% CI 14.5-25.1) than in those who received chemotherapy alone (13.8 months; 95% CI 10.8-16.9). The immune profiling of the tumors in resected patients revealed higher scores of CD8+ T cells to Tregs in patients with add-on nivolumab comparing to those who received chemotherapy alone.
Conclusion: Adding-on nivolumab was associated with improved OS in patients with advanced PDAC who achieved disease control following chemotherapy.
背景:由于疗效甚微,免疫检查点抑制剂(ICIs)很少用于治疗晚期胰腺导管腺癌(PDAC):本研究纳入了92例连续确诊为晚期或复发性PDAC的患者,这些患者接受了基于nivolumab的治疗。采用单变量和多变量分析确定预后因素。使用倾向评分匹配法(PSM)选择了301名接受姑息化疗但未使用ICIs的PDAC患者作为对照组进行比较:nivolumab治疗后的中位总生存期(OS)分别为15.8个月(95%置信区间[CI],12.5-19.0)、2.4个月(95% CI,1.2-3.6)和1.1个月(95% CI,1.0-1.2)。在化疗达到疾病控制后接受附加尼妥珠单抗治疗的患者中,在未确认疾病控制的前提下同时接受尼妥珠单抗和化疗的患者中,以及在未同时接受化疗的情况下接受尼妥珠单抗治疗的患者中,尼妥珠单抗对Tregs的影响分别为1.1(95% CI 1.0-1.2)个月、2.4(95% CI 1.2-3.6)个月和1.1(95% CI 1.0-1.2)个月:在化疗后病情得到控制的晚期PDAC患者中,加用nivolumab与OS的改善有关。
{"title":"Adding-on nivolumab to chemotherapy-stabilized patients is associated with improved survival in advanced pancreatic ductal adenocarcinoma.","authors":"Shih-Hung Yang, Sung-Hsin Kuo, Jen-Chieh Lee, Bang-Bin Chen, Yan-Shen Shan, Yu-Wen Tien, Sz-Chi Chiu, Ann-Lii Cheng, Kun-Huei Yeh","doi":"10.1007/s00262-024-03821-3","DOIUrl":"10.1007/s00262-024-03821-3","url":null,"abstract":"<p><strong>Background: </strong>Immune checkpoint inhibitors (ICIs) are rarely used to treat advanced pancreatic ductal adenocarcinoma (PDAC) due to marginal efficacy.</p><p><strong>Patients and methods: </strong>This study included 92 consecutive patients diagnosed with advanced or recurrent PDAC who received nivolumab-based treatment. Univariate and multivariate analyses were used to identify prognostic factors. A control group of 301 patients with PDAC who achieved disease control with palliative chemotherapy but without ICIs was selected for comparison using propensity score matching (PSM).</p><p><strong>Results: </strong>The median overall survival (OS) since nivolumab treatment was 15.8 (95% confidence interval [CI], 12.5-19.0), 2.4 (95% CI 1.2-3.6), and 1.1 (95% CI 1.0-1.2) months in patients who received add-on nivolumab after achieving disease control with chemotherapy, in those who received concomitant nivolumab and chemotherapy without prerequisite confirmation of disease control, and in those who received nivolumab without concomitant chemotherapy, respectively (P < 0.001). After PSM, the median overall survival (OS) since initiation of the concomitant chemotherapy that achieved disease control was significantly longer (P = 0.026) in patients who received add-on nivolumab (19.8 months; 95% CI 14.5-25.1) than in those who received chemotherapy alone (13.8 months; 95% CI 10.8-16.9). The immune profiling of the tumors in resected patients revealed higher scores of CD8<sup>+</sup> T cells to Tregs in patients with add-on nivolumab comparing to those who received chemotherapy alone.</p><p><strong>Conclusion: </strong>Adding-on nivolumab was associated with improved OS in patients with advanced PDAC who achieved disease control following chemotherapy.</p>","PeriodicalId":9595,"journal":{"name":"Cancer Immunology, Immunotherapy","volume":"73 11","pages":"227"},"PeriodicalIF":4.6,"publicationDate":"2024-09-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11383886/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142153182","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}