Laboratory for Immunotherapy, RIKEN Center for Integrative Medical Sciences, Yokohama, Japan.
RIKEN Program for Drug Discovery and Medical Technology Platforms, RIKEN, Yokohama, Japan.
Cancer Res. 2024 Sep 4;84(17):2792-2805. doi: 10.1158/0008-5472.CAN-23-2846.
Neoantigen-based immunotherapy is an attractive potential treatment for previously intractable tumors. To effectively broaden the application of this approach, stringent biomarkers are crucial to identify responsive patients. ARID1A, a frequently mutated subunit of SWI/SNF chromatin remodeling complex, has been reported to determine tumor immunogenicity in some cohorts; however, mutations and deletions of ARID1A are not always linked to clinical responses to immunotherapy. In this study, we investigated immunotherapeutic responses based on ARID1A status in targeted therapy-resistant cancers. Mouse and human BRAFV600E melanomas with or without ARID1A expression were transformed into resistant to vemurafenib, an FDA-approved specific BRAFV600E inhibitor. Anti-PD-1 antibody treatment enhanced antitumor immune responses in vemurafenib-resistant ARID1A-deficient tumors but not in ARID1A-intact tumors or vemurafenib-sensitive ARID1A-deficient tumors. Neoantigens derived from accumulated somatic mutations during vemurafenib resistance were highly expressed in ARID1A-deficient tumors and promoted tumor immunogenicity. Furthermore, the newly generated neoantigens could be utilized as immunotherapeutic targets by vaccines. Finally, targeted therapy resistance-specific neoantigen in experimental human melanoma cells lacking ARID1A were validated to elicit T-cell receptor responses. Collectively, the classification of ARID1A-mutated tumors based on vemurafenib resistance as an additional indicator of immunotherapy response will enable a more accurate prediction to guide cancer treatment. Furthermore, the neoantigens that emerge with therapy resistance can be promising therapeutic targets for refractory tumors. Significance: Chemotherapy resistance promotes the acquisition of immunogenic neoantigens in ARID1A-deficient tumors that confer sensitivity to immune checkpoint blockade and can be utilized for developing antitumor vaccines, providing strategies to improve immunotherapy efficacy.
基于新抗原的免疫疗法是一种有吸引力的潜在治疗方法，可用于以前难以治疗的肿瘤。为了有效地扩大这种方法的应用范围，严格的生物标志物对于识别有反应的患者至关重要。ARID1A 是 SWI/SNF 染色质重塑复合物的一个经常发生突变的亚基，已在一些队列中被报道决定肿瘤的免疫原性；然而，ARID1A 的突变和缺失并不总是与免疫治疗的临床反应相关。在这项研究中，我们根据 ARID1A 状态研究了靶向治疗耐药性癌症中的免疫治疗反应。具有或不具有 ARID1A 表达的小鼠和人类 BRAFV600E 黑色素瘤被转化为对vemurafenib（一种 FDA 批准的特定 BRAFV600E 抑制剂）耐药。抗 PD-1 抗体治疗增强了 vemurafenib 耐药性 ARID1A 缺陷肿瘤中的抗肿瘤免疫反应，但在 ARID1A 完整肿瘤或 vemurafenib 敏感的 ARID1A 缺陷肿瘤中没有增强。在 vemurafenib 耐药过程中积累的体细胞突变产生的新抗原在 ARID1A 缺陷肿瘤中高度表达，并促进了肿瘤的免疫原性。此外，新产生的新抗原可以作为疫苗的免疫治疗靶点。最后，在缺乏 ARID1A 的实验性人类黑色素瘤细胞中验证了靶向治疗耐药性特有的新抗原，以引发 T 细胞受体反应。总之，将基于 vemurafenib 耐药性的 ARID1A 突变肿瘤分类为免疫治疗反应的另一个指标，将能够更准确地预测指导癌症治疗。此外，随着治疗耐药性出现的新抗原可以成为难治性肿瘤有希望的治疗靶点。意义：化疗耐药性促进了 ARID1A 缺陷肿瘤中免疫原性新抗原的获得，使这些肿瘤对免疫检查点阻断敏感，并可用于开发抗肿瘤疫苗，为提高免疫治疗效果提供了策略。
