1. ARID1A-Deficient Tumors Acquire Immunogenic Neoantigens during the Development of Resistance to Targeted Therapy.
- Author
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Okada M, Yamasaki S, Nakazato H, Hirahara Y, Ishibashi T, Kawamura M, Shimizu K, and Fujii SI
- Subjects
- Animals, Humans, Mice, Immunotherapy methods, Proto-Oncogene Proteins B-raf genetics, Proto-Oncogene Proteins B-raf immunology, Cell Line, Tumor, Female, Immune Checkpoint Inhibitors pharmacology, Immune Checkpoint Inhibitors therapeutic use, Mutation, Molecular Targeted Therapy methods, Mice, Inbred C57BL, Transcription Factors genetics, Transcription Factors immunology, DNA-Binding Proteins genetics, DNA-Binding Proteins immunology, Drug Resistance, Neoplasm immunology, Antigens, Neoplasm immunology, Antigens, Neoplasm genetics, Vemurafenib pharmacology, Vemurafenib therapeutic use, Melanoma immunology, Melanoma drug therapy, Melanoma genetics, Melanoma therapy
- Abstract
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., (©2024 American Association for Cancer Research.)
- Published
- 2024
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