Mutations Associated with Acquired Resistance to PD-1 Blockade in Melanoma

Abstract

BACKGROUND Approximately 75% of objective responses to anti–programmed death 1 (PD-1) therapy in patients with melanoma are durable, lasting for years, but delayed relapses have been noted long after initial objective tumor regression despite continuous therapy. Mechanisms of immune escape in this context are unknown. METHODS We analyzed biopsy samples from paired baseline and relapsing lesions in four patients with metastatic melanoma who had had an initial objective tumor regression in response to anti–PD-1 therapy (pembrolizumab) followed by disease progression months to years later. RESULTS Whole-exome sequencing detected clonal selection and outgrowth of the acquired resistant tumors and, in two of the four patients, revealed resistance-associated loss-of-function mutations in the genes encoding interferon-receptor–associated Janus kinase 1 (JAK1) or Janus kinase 2 (JAK2), concurrent with deletion of the wild-type allele. A truncating mutation in the gene encoding the antigen-presenting protein beta-2-microglobulin (B2M) was identified in a third patient. JAK1 and JAK2 truncating mutations resulted in a lack of response to interferon gamma, including insensitivity to its antiproliferative effects on cancer cells. The B2M truncating mutation led to loss of surface expression of major histocompatibility complex class I. CONCLUSIONS In this study, acquired resistance to PD-1 blockade immunotherapy in patients with melanoma was associated with defects in the pathways involved in interferon-receptor signaling and in antigen presentation. (Funded by the National Institutes of Health and others.)

Transient immunological and clinical effectiveness of treating mice bearing premalignant oral lesions with PD‐1 antibodies

“…Similarly, blocking PD‐1 in patients with non‐small‐cell lung cancer prolonged progression‐free survival, but cancer nevertheless progressed in almost all patients 25. The most direct consistency with the present study's demonstration of a transient immunological response to PD‐1 blockade is demonstration of acquired resistance to PD‐1 antibody treatment in melanoma patients 43. This development of resistance was shown to be associated with alterations interferon receptor signaling and in antigen presentation.…”

Combination with SGT-53 overcomes tumor resistance to a checkpoint inhibitor

“…A recent study found that mutations that affected the antigen presentation and the sensitivity of tumor cells to T cell-derived IFNs could cause acquired resistance to anti-PD1 therapy. 4,48 To overcome, or potentially prevent, the development of acquired immunotherapeutic resistance, a very large number of trials are now underway that combine checkpoint blockade with a wide range of other agents. 10 In many cases, the combination under study appears to be lacking any strong mechanistic rationale for that particular combination.…”

Targeted agents and immunotherapies: optimizing outcomes in melanoma

“…Analyses of tumours with a very low IFNγ-associated geneexpression score, or a 'non-T-cell-inflamed' tumour microenvironment have revealed roles for activation of the WNT/β-catenin-signalling pathway 145 , and an enrichment for mutations in PTEN 146 in immune evasion. Deleterious mutations in the genes encoding JAK1 and JAK2 (which are involved in IFNγ signalling), or β 2 microglobulin (an MHC class I subunit), as well as loss of expression of interferon regulatory factor 1 (IRF1) have also been described in anti-PD-1-antibody-resistant patient samples and cell lines 147,148 . These intratumoural changes are associated with deficits in autophagy, antigen presentation, and the type I interferon response, suggesting that rational drug combinations should be explored to either suppress these pathways using β-catenin or PI3Kβ inhibitors, and/or amplify antigen presentation, perhaps via an approach such as FLT3-ligand agonism.…”