| RRC ID |
81653
|
| Author |
Okada M, Yamasaki S, Nakazato H, Hirahara Y, Ishibashi T, Kawamura M, Shimizu K, Fujii SI.
|
| Title |
ARID1A-Deficient Tumors Acquire Immunogenic Neoantigens during the Development of Resistance to Targeted Therapy.
|
| Journal |
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.
|
| Volume |
84(17)
|
| Pages |
2792-2805
|
| Published |
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
|
| Resource |
| Human and Animal Cells |
293T(RCB2202)
SKW-3(RCB1168) |
