論文 - 詳細
| RRC ID | 81653 |
|---|---|
| 著者 | Okada M, Yamasaki S, Nakazato H, Hirahara Y, Ishibashi T, Kawamura M, Shimizu K, Fujii SI. |
| タイトル | ARID1A-Deficient Tumors Acquire Immunogenic Neoantigens during the Development of Resistance to Targeted Therapy. |
| ジャーナル | Cancer Res |
| 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. |
| 巻・号 | 84(17) |
| ページ | 2792-2805 |
| 公開日 | 2024-9-4 |
| DOI | 10.1158/0008-5472.CAN-23-2846 |
| PII | 747057 |
| PMID | 39228255 |
| MeSH | Animals Antigens, Neoplasm* / genetics Antigens, Neoplasm* / immunology Cell Line, Tumor DNA-Binding Proteins* / genetics DNA-Binding Proteins* / immunology Drug Resistance, Neoplasm* / immunology Female Humans Immune Checkpoint Inhibitors / pharmacology Immune Checkpoint Inhibitors / therapeutic use Immunotherapy / methods Melanoma* / drug therapy Melanoma* / genetics Melanoma* / immunology Melanoma* / therapy Mice Mice, Inbred C57BL Molecular Targeted Therapy / methods Mutation Proto-Oncogene Proteins B-raf / genetics Proto-Oncogene Proteins B-raf / immunology Transcription Factors* / genetics Transcription Factors* / immunology Vemurafenib* / pharmacology Vemurafenib* / therapeutic use |
| IF | 9.727 |
| オルトメトリクス指標 |
オルトメトリクス指標項目
|
| 最多言及媒体 | X(Twitter) |
| 各媒体での言及数の合計 | 9 |
| 過去6か月間でのオルトメトリクス指標の変動値 | 0.0 |
| リソース情報 | |
| ヒト・動物細胞 | 293T(RCB2202) SKW-3(RCB1168) |