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

By J. Zaretsky, A. García-Díaz, D. Shin, Helena Escuin-Ordinas, Willy Hugo, S. Hu-Lieskovan, D. Torrejon, Gabriel Abril-Rodriguez, Salemiz Sandoval, Lucas Barthly and 19 more. New England Journal of Medicine, 2016

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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.)

Subfields: Molecular Biology, Oncology

View Paper: https://www.semanticscholar.org/paper/b159cdd0b04a2080dda3822f73e2fe2acff4d83d

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Citations in the corpus

Anti-PD-1 and Anti-CTLA-4 Therapies in Cancer: Mechanisms of Action, Efficacy, and Limitations (2018, background): “Cancer Immunol Immunother (2013) 62(6):1021–8.”
Cooperation between Constitutive and Inducible Chemokines Enables T-cell Engraftment and Immune Attack in Solid Tumors (2019, background): “, 2014), and explain observations where loss of the antigen presentation machinery is associated with TILs loss in cancers (Angelova et al., 2018; Zaretsky et al., 2016).”
Tumor Interferon Signaling Regulates a Multigenic Resistance Program to Immune Checkpoint Blockade (2016, neutral): “In both cases, it has been suggested that such genetic events may be selected to circumvent IFN-mediated cytostasis and cytotoxicity (Gao et al., 2016; Zaretsky et al., 2016), resulting in these tumors failing or relapsing after ICB due to reliance on IFN-regulated antigen processing or other positi”
Machine Learning Identifies Stemness Features Associated with Oncogenic Dedifferentiation (2018, result): “Our ﬁndings are consistent with previous reports showing a strong correlation between PD-L1 protein expression and inﬁltration of CD8+ cytotoxic lymphocytes (Zaretsky et al., 2016).”
Evolution of neoantigen landscape during immune checkpoint blockade in non-small cell lung cancer (2016, background): “Likewise, we did not observe any loss-of-function mutations or LOH in genes related to other reported mechanisms of resistance, including HLA genes ( 13 ), β2-microglobulin ( 15 ), PTEN ( 19 ), JAK1 , and JAK2 ( 15 ), or the transporter for antigen presentation ( TAP1 ) gene in the resistance tumor ”
Hyper-progressors after Immunotherapy: Analysis of Genomic Alterations Associated with Accelerated Growth Rate (2017, background): “Other resistance alterations that have been described include JAK1- or JAK2-inactivating alterations and beta-2-microglobulin truncation (7).”
Interferon-Gamma at the Crossroads of Tumor Immune Surveillance or Evasion (2018, background): “Recent reports suggest that loss of IFN-γ pathway genes, such as JAK1 and JAK2, is associated with resistance to anti-PD-1 therapy (257, 258).”