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.

中文翻译：

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ARID1A 缺陷型肿瘤在对靶向治疗的耐药性发展过程中获得免疫原性新抗原


基于新抗原的免疫疗法是治疗既往难治性肿瘤的一种有吸引力的潜在治疗方法。为了有效地扩大这种方法的应用，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种经常突变的亚基，据报道可确定某些队列中的肿瘤免疫原性;然而，ARID1A 的突变和缺失并不总是与对免疫治疗的临床反应有关。在这项研究中，我们调查了靶向治疗耐药癌症中基于 ARID1A 状态的免疫治疗反应。具有或不具有 ARID1A 表达的小鼠和人BRAFV600E黑色素瘤转化为对 vemurafenib（一种 FDA 批准的特异性BRAFV600E抑制剂）的耐药性。抗 PD-1 抗体治疗增强了维罗非尼耐药 ARID1A 缺陷型肿瘤的抗肿瘤免疫反应，但在 ARID1A 完整肿瘤或维罗非尼敏感的 ARID1A 缺陷型肿瘤中未增强抗肿瘤免疫反应。维罗非尼耐药期间积累的体细胞突变衍生的新抗原在 ARID1A 缺陷型肿瘤中高表达并促进肿瘤免疫原性。此外，新产生的新抗原可以用作疫苗的免疫治疗靶点。最后，在缺乏 ARID1A 的实验性人黑色素瘤细胞中验证靶向治疗耐药特异性新抗原可引发 T 细胞受体反应。总的来说，基于 vemurafenib 耐药性作为免疫治疗反应的附加指标对 ARID1A 突变的肿瘤进行分类，将能够更准确地预测以指导癌症治疗。此外，随着治疗耐药性出现的新抗原可能成为难治性肿瘤的有希望的治疗靶点。 意义： 化疗耐药性促进 ARID1A 缺陷型肿瘤中免疫原性新抗原的获得，这些新抗原赋予对免疫检查点阻断的敏感性，可用于开发抗肿瘤疫苗，为提高免疫治疗效果提供策略。