Coexisting Alterations of MHC Class I Antigen Presentation and IFNg Signaling Mediate Acquired Resistance of Melanoma to Post-PD-1 Immunotherapy

Responses to immunotherapy can be very durable but acquired resistance leading to tumor progression often occurs. We investi-gated 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 objec-tive 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 thorn tumor-infiltrating lymphocytes (TIL; B2M loss) and CD4 thorn 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.

Automated summary

This study investigated a melanoma patient resistant to anti-PD-1 treatment and found consecutive acquisition of B2M loss and impaired JAK1 signaling, leading to immune escape of tumor cells. These findings shed light on the complexity of acquired resistance to immunotherapy and suggest that coexisting altered pathways can result in pan T-cell immune escape.