Coexisting Alterations of MHC Class I Antigen Presentation and IFNg Signaling Mediate Acquired Resistance of Melanoma to Post-PD-1 Immunotherapy
Research output: Contribution to journal › Journal article › Research › peer-review
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.
Original language | English |
---|---|
Journal | Cancer Immunology Research |
Volume | 10 |
Issue number | 10 |
Pages (from-to) | 1254-1262 |
Number of pages | 9 |
ISSN | 2326-6066 |
DOIs | |
Publication status | Published - 2022 |
Bibliographical note
Publisher Copyright:
© 2022 American Association for Cancer Research.
ID: 340412557