Yue Wang, Mengying Hu, Olivera J Finn, Xiao-Song Wang
{"title":"肿瘤相关抗原负担与免疫检查点阻断剂在T细胞耗竭水平较低的肿瘤中的获益相关。","authors":"Yue Wang, Mengying Hu, Olivera J Finn, Xiao-Song Wang","doi":"10.1158/2326-6066.CIR-23-0932","DOIUrl":null,"url":null,"abstract":"<p><p>Tumor-associated antigens (TAA) are important targets for cancer vaccines. However, TAA-based vaccines have not yet achieved their full potential in clinical trials. In contrast, immune checkpoint blockade (ICB) has emerged as an effective therapy, leading to durable responses in selected patients with cancer. To date, few generalizable associations between TAAs and ICB benefit have been reported, with most studies focusing on melanoma, which has the highest mutation rate in cancer. In this study, we developed a TAA burden (TAB) algorithm based on known and putative TAAs and investigated the association of TAB with ICB benefit. Analysis of the IMvigor210 patient cohort of urothelial carcinoma treated with anti-PDL1 revealed that high tumor mutation burden weakened the association of TAB with ICB benefit. Furthermore, TAB correlated with ICB efficacy in tumors characterized by negative PDL1 staining on immune cells; however, high levels of PDL1 staining on immune cells were linked to T-cell exhaustion. Validation across independent clinical datasets-including urothelial carcinoma cohorts treated with anti-PD1/PDL1 agents and neoadjuvant anti-PD1 trials for head and neck cancers-corroborated the finding that TAB correlates with ICB benefit in tumors with low T-cell exhaustion. Pan-cancer analyses revealed that in most cancer entities, tumors with higher T-cell exhaustion exhibited lower TAB levels, implying possible immunoediting of TAAs in tumors with established antitumor immunity. Our study challenges the prevailing notion of a lack of association between TAAs and ICB response. It also underscores the need for future investigations into the immunogenicity of TAAs and TAA-based vaccine strategies in tumors with low levels of T-cell exhaustion.</p>","PeriodicalId":9474,"journal":{"name":"Cancer immunology research","volume":null,"pages":null},"PeriodicalIF":8.1000,"publicationDate":"2024-11-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11534523/pdf/","citationCount":"0","resultStr":"{\"title\":\"Tumor-Associated Antigen Burden Correlates with Immune Checkpoint Blockade Benefit in Tumors with Low Levels of T-cell Exhaustion.\",\"authors\":\"Yue Wang, Mengying Hu, Olivera J Finn, Xiao-Song Wang\",\"doi\":\"10.1158/2326-6066.CIR-23-0932\",\"DOIUrl\":null,\"url\":null,\"abstract\":\"<p><p>Tumor-associated antigens (TAA) are important targets for cancer vaccines. However, TAA-based vaccines have not yet achieved their full potential in clinical trials. In contrast, immune checkpoint blockade (ICB) has emerged as an effective therapy, leading to durable responses in selected patients with cancer. To date, few generalizable associations between TAAs and ICB benefit have been reported, with most studies focusing on melanoma, which has the highest mutation rate in cancer. In this study, we developed a TAA burden (TAB) algorithm based on known and putative TAAs and investigated the association of TAB with ICB benefit. Analysis of the IMvigor210 patient cohort of urothelial carcinoma treated with anti-PDL1 revealed that high tumor mutation burden weakened the association of TAB with ICB benefit. Furthermore, TAB correlated with ICB efficacy in tumors characterized by negative PDL1 staining on immune cells; however, high levels of PDL1 staining on immune cells were linked to T-cell exhaustion. Validation across independent clinical datasets-including urothelial carcinoma cohorts treated with anti-PD1/PDL1 agents and neoadjuvant anti-PD1 trials for head and neck cancers-corroborated the finding that TAB correlates with ICB benefit in tumors with low T-cell exhaustion. Pan-cancer analyses revealed that in most cancer entities, tumors with higher T-cell exhaustion exhibited lower TAB levels, implying possible immunoediting of TAAs in tumors with established antitumor immunity. Our study challenges the prevailing notion of a lack of association between TAAs and ICB response. 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Tumor-Associated Antigen Burden Correlates with Immune Checkpoint Blockade Benefit in Tumors with Low Levels of T-cell Exhaustion.
Tumor-associated antigens (TAA) are important targets for cancer vaccines. However, TAA-based vaccines have not yet achieved their full potential in clinical trials. In contrast, immune checkpoint blockade (ICB) has emerged as an effective therapy, leading to durable responses in selected patients with cancer. To date, few generalizable associations between TAAs and ICB benefit have been reported, with most studies focusing on melanoma, which has the highest mutation rate in cancer. In this study, we developed a TAA burden (TAB) algorithm based on known and putative TAAs and investigated the association of TAB with ICB benefit. Analysis of the IMvigor210 patient cohort of urothelial carcinoma treated with anti-PDL1 revealed that high tumor mutation burden weakened the association of TAB with ICB benefit. Furthermore, TAB correlated with ICB efficacy in tumors characterized by negative PDL1 staining on immune cells; however, high levels of PDL1 staining on immune cells were linked to T-cell exhaustion. Validation across independent clinical datasets-including urothelial carcinoma cohorts treated with anti-PD1/PDL1 agents and neoadjuvant anti-PD1 trials for head and neck cancers-corroborated the finding that TAB correlates with ICB benefit in tumors with low T-cell exhaustion. Pan-cancer analyses revealed that in most cancer entities, tumors with higher T-cell exhaustion exhibited lower TAB levels, implying possible immunoediting of TAAs in tumors with established antitumor immunity. Our study challenges the prevailing notion of a lack of association between TAAs and ICB response. It also underscores the need for future investigations into the immunogenicity of TAAs and TAA-based vaccine strategies in tumors with low levels of T-cell exhaustion.
期刊介绍:
Cancer Immunology Research publishes exceptional original articles showcasing significant breakthroughs across the spectrum of cancer immunology. From fundamental inquiries into host-tumor interactions to developmental therapeutics, early translational studies, and comprehensive analyses of late-stage clinical trials, the journal provides a comprehensive view of the discipline. In addition to original research, the journal features reviews and opinion pieces of broad significance, fostering cross-disciplinary collaboration within the cancer research community. Serving as a premier resource for immunology knowledge in cancer research, the journal drives deeper insights into the host-tumor relationship, potent cancer treatments, and enhanced clinical outcomes.
Key areas of interest include endogenous antitumor immunity, tumor-promoting inflammation, cancer antigens, vaccines, antibodies, cellular therapy, cytokines, immune regulation, immune suppression, immunomodulatory effects of cancer treatment, emerging technologies, and insightful clinical investigations with immunological implications.