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":null,"pages":null},"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":null,"pages":null},"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":null,"pages":null},"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":null,"pages":null},"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":null,"pages":null},"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":null,"pages":null},"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":null,"pages":null},"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}
Pub Date : 2024-09-09DOI: 10.1007/s00262-024-03809-z
Tara Muijlwijk, Niels E Wondergem, Fatima Ekhlas, Naomi Remkes, Dennis N L M Nijenhuis, Lennart Fritz, Sonja H Ganzevles, Iris H C Miedema, C René Leemans, Jos B Poell, Ruud H Brakenhoff, Rieneke van de Ven
Immune checkpoint inhibitors are approved for recurrent/metastatic head and neck squamous cell carcinoma (HNSCC) but the response rate is only 13-18%. For an effective antitumor immune response, trafficking of immune cells to the tumor microenvironment (TME) is essential. We aimed to better understand immune cell migration as well as the involved chemokines in HNSCC. A transwell assay was used to study immune cell migration toward TME-conditioned medium. While T cell migration was not observed, conventional dendritic cell (cDC) migration was induced by TME-conditioned media. cDC migration correlated with various proteins in the TME secretome. CCL8, CXCL5, CCL13 and CCL7 were tested in validation experiments and addition of these chemokines induced cDC migration. Using single cell RNA-sequencing, we observed expression of CCL8, CXCL5, CCL13 and CCL7 in cancer-associated fibroblasts (CAFs). Depleting fibroblasts led to reduced cDC migration. Thus CAFs, while often seen as suppressors of antitumor immunity, play a role in attracting cDCs toward the head and neck cancer TME, which might be crucial for effective antitumor immunity and response to therapies. Indeed, we found RNA expression signatures of the indicated chemokines, cDC and CAF subpopulations, to be significantly higher in baseline tumor specimen of patients with a major pathological response to pre-surgical anti-PD-1 treatment compared to non-responding patients.
{"title":"Secretome and immune cell attraction analysis of head and neck cancers.","authors":"Tara Muijlwijk, Niels E Wondergem, Fatima Ekhlas, Naomi Remkes, Dennis N L M Nijenhuis, Lennart Fritz, Sonja H Ganzevles, Iris H C Miedema, C René Leemans, Jos B Poell, Ruud H Brakenhoff, Rieneke van de Ven","doi":"10.1007/s00262-024-03809-z","DOIUrl":"10.1007/s00262-024-03809-z","url":null,"abstract":"<p><p>Immune checkpoint inhibitors are approved for recurrent/metastatic head and neck squamous cell carcinoma (HNSCC) but the response rate is only 13-18%. For an effective antitumor immune response, trafficking of immune cells to the tumor microenvironment (TME) is essential. We aimed to better understand immune cell migration as well as the involved chemokines in HNSCC. A transwell assay was used to study immune cell migration toward TME-conditioned medium. While T cell migration was not observed, conventional dendritic cell (cDC) migration was induced by TME-conditioned media. cDC migration correlated with various proteins in the TME secretome. CCL8, CXCL5, CCL13 and CCL7 were tested in validation experiments and addition of these chemokines induced cDC migration. Using single cell RNA-sequencing, we observed expression of CCL8, CXCL5, CCL13 and CCL7 in cancer-associated fibroblasts (CAFs). Depleting fibroblasts led to reduced cDC migration. Thus CAFs, while often seen as suppressors of antitumor immunity, play a role in attracting cDCs toward the head and neck cancer TME, which might be crucial for effective antitumor immunity and response to therapies. Indeed, we found RNA expression signatures of the indicated chemokines, cDC and CAF subpopulations, to be significantly higher in baseline tumor specimen of patients with a major pathological response to pre-surgical anti-PD-1 treatment compared to non-responding patients.</p>","PeriodicalId":9595,"journal":{"name":"Cancer Immunology, Immunotherapy","volume":null,"pages":null},"PeriodicalIF":4.6,"publicationDate":"2024-09-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11383899/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142153185","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}
Background: Adjuvant nivolumab reduces recurrence in patients with locoregional esophageal cancer who had pathological residual disease after neoadjuvant chemoradiotherapy and R0 resection. However, the efficacy of adjuvant anti-PD-1 therapy in patients at higher risk of recurrence remains unclear.
Methods: This phase II trial (ClinicalTrials.gov identifier: NCT03322267) enrolled patients with locally advanced esophageal squamous cell carcinoma (ESCC) received neoadjuvant chemoradiotherapy plus esophagectomy but still had various risk factors for recurrence, such as involved or close margins (≤ 1 mm), extranodal extension of the involved lymph nodes, and the ypN2-3 stage. Patients received adjuvant therapy composed of a course of cisplatin-based chemoradiotherapy and pembrolizumab (200 mg, IV every 3 weeks) for 18 cycles. The primary endpoint was 1-year relapse-free survival (RFS) rate.
Results: Twenty-five patients were enrolled. The risk factors were tumor margins of ≤ 1 mm (18 patients), extranodal extension of the involved lymph nodes (9 patients), and the ypN2-3 stage (9 patients). The median follow-up duration was 21.6 months (95% CI: 18.7-33.2). The rate of 1-year RFS was 60.0%. The median duration of RFS and overall survival was 14.3 (95% CI: 9.0-19.5) and 21.6 (95% CI: 0.0-45.5) months, respectively. Treatment-emergent adverse events of any grade and those of ≥ 3 grade occurred in 56% and 8% of all patients receiving cisplatin-based chemoradiotherapy and in 79.2% and 12.5% of those receiving pembrolizumab.
Conclusions: Adjuvant chemoradiotherapy followed by pembrolizumab is feasible and may be associated with improved 1-year RFS rate in patients at high risk of recurrence after trimodality therapy for locally advanced ESCC. Trial registration number ClinicalTrials.gov (No. NCT03322267).
{"title":"Adjuvant chemoradiotherapy plus pembrolizumab for locally advanced esophageal squamous cell carcinoma with high risk of recurrence following neoadjuvant chemoradiotherapy: a single-arm phase II study.","authors":"Jhe-Cyuan Guo, Ta-Chen Huang, Hung-Yang Kuo, Chia-Chi Lin, Feng-Ming Hsu, Jason Chia-Hsien Cheng, Yen-Lin Huang, Min-Shu Hsieh, Pei-Ming Huang, Jang-Ming Lee, Shu-Ling Wu, Chih-Hung Hsu","doi":"10.1007/s00262-024-03826-y","DOIUrl":"10.1007/s00262-024-03826-y","url":null,"abstract":"<p><strong>Background: </strong>Adjuvant nivolumab reduces recurrence in patients with locoregional esophageal cancer who had pathological residual disease after neoadjuvant chemoradiotherapy and R0 resection. However, the efficacy of adjuvant anti-PD-1 therapy in patients at higher risk of recurrence remains unclear.</p><p><strong>Methods: </strong>This phase II trial (ClinicalTrials.gov identifier: NCT03322267) enrolled patients with locally advanced esophageal squamous cell carcinoma (ESCC) received neoadjuvant chemoradiotherapy plus esophagectomy but still had various risk factors for recurrence, such as involved or close margins (≤ 1 mm), extranodal extension of the involved lymph nodes, and the ypN2-3 stage. Patients received adjuvant therapy composed of a course of cisplatin-based chemoradiotherapy and pembrolizumab (200 mg, IV every 3 weeks) for 18 cycles. The primary endpoint was 1-year relapse-free survival (RFS) rate.</p><p><strong>Results: </strong>Twenty-five patients were enrolled. The risk factors were tumor margins of ≤ 1 mm (18 patients), extranodal extension of the involved lymph nodes (9 patients), and the ypN2-3 stage (9 patients). The median follow-up duration was 21.6 months (95% CI: 18.7-33.2). The rate of 1-year RFS was 60.0%. The median duration of RFS and overall survival was 14.3 (95% CI: 9.0-19.5) and 21.6 (95% CI: 0.0-45.5) months, respectively. Treatment-emergent adverse events of any grade and those of ≥ 3 grade occurred in 56% and 8% of all patients receiving cisplatin-based chemoradiotherapy and in 79.2% and 12.5% of those receiving pembrolizumab.</p><p><strong>Conclusions: </strong>Adjuvant chemoradiotherapy followed by pembrolizumab is feasible and may be associated with improved 1-year RFS rate in patients at high risk of recurrence after trimodality therapy for locally advanced ESCC. Trial registration number ClinicalTrials.gov (No. NCT03322267).</p>","PeriodicalId":9595,"journal":{"name":"Cancer Immunology, Immunotherapy","volume":null,"pages":null},"PeriodicalIF":4.6,"publicationDate":"2024-09-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11383884/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142153183","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 : 2024-09-09DOI: 10.1007/s00262-024-03822-2
Salvatore Lorenzo Renne, Laura Sama', Sonia Kumar, Omer Mintemur, Laura Ruspi, Ilaria Santori, Federico Sicoli, Alexia Bertuzzi, Alice Laffi, Arturo Bonometti, Piergiuseppe Colombo, Vittoria D'amato, Alessandra Bressan, Marta Scorsetti, Luigi Terracciano, Pierina Navarria, Maurizio D'incalci, Vittorio Quagliuolo, Fabio Pasqualini, Fabio Grizzi, Ferdinando Carlo Maria Cananzi
Background: The antigen processing machinery (APM) plays a critical role in generating tumor-specific antigens that can be recognized and targeted by the immune system. Proper functioning of APM components is essential for presenting these antigens on the surface of tumor cells, enabling immune detection and destruction. In many cancers, defects in APM can lead to immune evasion, contributing to tumor progression and poor clinical outcomes. However, the status of the APM in sarcomas is not well characterized, limiting the development of effective immunotherapeutic strategies for these patients.
Methods: We investigated 126 patients with 8 types of bone and soft tissue sarcoma operated between 2001-2021. Tissue microarrays mapped 11 specific areas in each case. The presence/absence of APM protein was determined through immunohistochemistry. Bayesian networks were used.
Results: All investigated sarcomas had some defects in APM. The least damaged component was HLA Class I subunit β2-microglobulin and HLA Class II. The proteasome LMP10 subunit was defective in leiomyosarcoma (LMS), myxoid liposarcoma (MLPS), and dedifferentiated liposarcoma (DDLPS), while MHC I transporting unit TAP2 was altered in undifferentiated pleomorphic sarcoma (UPS), gastrointestinal stromal tumor (GIST), and chordoma (CH). Among different neoplastic areas, high-grade areas showed different patterns of expression compared to high lymphocytic infiltrate areas. Heterogeneity at the patient level was also observed. Loss of any APM component was prognostic of distant metastasis (DM) for LMS and DDLPS and of overall survival (OS) for LMS.
Conclusion: Sarcomas exhibit a high degree of defects in APM components, with differences among histotypes and tumoral areas. The most commonly altered APM components were HLA Class I subunit β2-microglobulin, HLA Class I subunit α (HC10), and MHC I transporting unit TAP2. The loss of APM components was prognostic of DM and OS and clinically relevant for LMS and DDLPS. This study explores sarcoma molecular mechanisms, enriching personalized therapeutic approaches.
{"title":"Disruptions in antigen processing and presentation machinery on sarcoma.","authors":"Salvatore Lorenzo Renne, Laura Sama', Sonia Kumar, Omer Mintemur, Laura Ruspi, Ilaria Santori, Federico Sicoli, Alexia Bertuzzi, Alice Laffi, Arturo Bonometti, Piergiuseppe Colombo, Vittoria D'amato, Alessandra Bressan, Marta Scorsetti, Luigi Terracciano, Pierina Navarria, Maurizio D'incalci, Vittorio Quagliuolo, Fabio Pasqualini, Fabio Grizzi, Ferdinando Carlo Maria Cananzi","doi":"10.1007/s00262-024-03822-2","DOIUrl":"10.1007/s00262-024-03822-2","url":null,"abstract":"<p><strong>Background: </strong>The antigen processing machinery (APM) plays a critical role in generating tumor-specific antigens that can be recognized and targeted by the immune system. Proper functioning of APM components is essential for presenting these antigens on the surface of tumor cells, enabling immune detection and destruction. In many cancers, defects in APM can lead to immune evasion, contributing to tumor progression and poor clinical outcomes. However, the status of the APM in sarcomas is not well characterized, limiting the development of effective immunotherapeutic strategies for these patients.</p><p><strong>Methods: </strong>We investigated 126 patients with 8 types of bone and soft tissue sarcoma operated between 2001-2021. Tissue microarrays mapped 11 specific areas in each case. The presence/absence of APM protein was determined through immunohistochemistry. Bayesian networks were used.</p><p><strong>Results: </strong>All investigated sarcomas had some defects in APM. The least damaged component was HLA Class I subunit β2-microglobulin and HLA Class II. The proteasome LMP10 subunit was defective in leiomyosarcoma (LMS), myxoid liposarcoma (MLPS), and dedifferentiated liposarcoma (DDLPS), while MHC I transporting unit TAP2 was altered in undifferentiated pleomorphic sarcoma (UPS), gastrointestinal stromal tumor (GIST), and chordoma (CH). Among different neoplastic areas, high-grade areas showed different patterns of expression compared to high lymphocytic infiltrate areas. Heterogeneity at the patient level was also observed. Loss of any APM component was prognostic of distant metastasis (DM) for LMS and DDLPS and of overall survival (OS) for LMS.</p><p><strong>Conclusion: </strong>Sarcomas exhibit a high degree of defects in APM components, with differences among histotypes and tumoral areas. The most commonly altered APM components were HLA Class I subunit β2-microglobulin, HLA Class I subunit α (HC10), and MHC I transporting unit TAP2. The loss of APM components was prognostic of DM and OS and clinically relevant for LMS and DDLPS. This study explores sarcoma molecular mechanisms, enriching personalized therapeutic approaches.</p>","PeriodicalId":9595,"journal":{"name":"Cancer Immunology, Immunotherapy","volume":null,"pages":null},"PeriodicalIF":4.6,"publicationDate":"2024-09-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11383888/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142153184","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}