Coexisting Alterations of MHC Class I Antigen Presentation and IFNg Signaling Mediate Acquired Resistance of Melanoma to Post-PD-1 Immunotherapy
Publikation: Bidrag til tidsskrift › Tidsskriftartikel › Forskning › fagfællebedømt
Responses to immunotherapy can be very durable but acquired resistance leading to tumor progression often occurs. We investigated a patient with melanoma resistant to anti-programmed death 1 (anti-PD-1) who participated in the CA224-020 clinical trial (NCT01968109) and had further progression after an initial objective response to anti-PD-1 plus anti-lymphocyte activation gene 3. We found consecutive acquisition of beta-2 microglobulin (B2M) loss and impaired Janus kinase 1 (JAK1) signaling that coexisted in progressing tumor cells. Functional analyses revealed a pan T-cell immune escape phenotype, where distinct alterations mediated independent immune resistance to tumor killing by autologous CD8+ tumor-infiltrating lymphocytes (TIL; B2M loss) and CD4+ TILs (impaired JAK1 signaling). These findings shed light on the complexity of acquired resistance to immunotherapy in the post anti-PD-1 setting, indicating that coexisting altered pathways can lead to pan T-cell immune escape.
| Originalsprog | Engelsk |
|---|---|
| Tidsskrift | Cancer Immunology Research |
| Vol/bind | 10 |
| Udgave nummer | 10 |
| Sider (fra-til) | 1254-1262 |
| Antal sider | 9 |
| ISSN | 2326-6066 |
| DOI | |
| Status | Udgivet - 2022 |
Bibliografisk note
Funding Information:
M. Nielsen reports grants and nonfinancial support from Bristol Myers Squibb; grants from Danish Cancer Society; and grants from Herlev and Gentofte Hospital during the conduct of the study. M. Presti reports grants from Danish Cancer Society, Herlev and Gentofte Hospital; and grants and nonfinancial support from Bristol Myers Squibb during the conduct of the study. A. Draghi reports grants and nonfinancial support from Bristol Myers Squibb; grants from Danish Cancer Society; and grants from Herlev and Gentofte Hospital during the conduct of the study. J. Wojcik reports other support from Bristol Myers Squibb outside the submitted work. I.M. Svane reports grants from Bristol Myers Squibb during the conduct of the study; personal fees from BMS, MSD, IO Biotech; and other support from IO Biotech
Funding Information:
The study was sponsored by Bristol Myers Squibb (Principal investigator: Inge Marie Svane). Additional funding was provided by Danish Cancer Society (grant number R288-A16337-B5238, to Mario Presti; and number R204-A12535, to Marco Donia) and Herlev and Gentofte Hospital (career development grant to Marco Donia).
Publisher Copyright:
© 2022 American Association for Cancer Research.
ID: 340412557