journal contribution posted on 2023-04-04, 01:41 authored by Morten Nielsen, Mario Presti, Zsofia Sztupinszki, Agnete Witness Præst Jensen, Arianna Draghi, Christopher Aled Chamberlain, Aimilia Schina, Christina Westmose Yde, John Wojcik, Zoltan Szallasi, Michael Douglas Crowther, Inge Marie Svane, Marco Donia
Supplementary Figure from Coexisting Alterations of MHC Class I Antigen Presentation and IFNγ Signaling Mediate Acquired Resistance of Melanoma to Post–PD-1 Immunotherapy
Danish Cancer Society
Bristol Myers Squibb
ARTICLE ABSTRACTResponses 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.