Mutations Associated with Acquired Resistance to PD-1 Blockade in Melanoma
Open accessAbstract
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.).
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Clinically relevant ICR mechanisms include B2M mutations causing MHC Class I loss, antigen presentation downregulation, and IFNγ-JAK/STAT mutations that impair response to T cell anti-tumor activity.
“Clinically relevant mechanisms of include mutations in beta-2-microglobulin (B2M) resulting in loss of MHC Class I presentation, downregulation of the antigen presentation machinery, and mutations in the IFNγ-JAK/STAT pathway that impair response to T cell mediated anti-tumor activity7–9.”
From Multimodal pooled Perturb-CITE-seq screens in patient models define mechanisms of cancer immune evasion (2021) · cites this paper as [7]
Perturbations of B2M, HLA-A, JAK1, JAK2, STAT1, IFNGR1, and IFNGR2 conferred immune evasion, consistent with clinical resistance mechanisms.
“perturbations of B2M, HLA-A, JAK1, JAK2, STAT1, IFNGR1 and IFNGR2 (Fig. 2d,e, Extended Data Fig. 3e,f, Supplementary Table 2) conferred immune evasion, consistent with clinical mechanisms of resistance to immunotherapy7–9.”
From Multimodal pooled Perturb-CITE-seq screens in patient models define mechanisms of cancer immune evasion (2021) · cites this paper as [7]
These findings are consistent with clinical data correlating resistance to checkpoint inhibitors with mutations in B2m and IFNγ pathways and with recent genome-wide CRISPR screening data.
“These findings are consistent with emerging clinical data correlating resistance to checkpoint inhibitors with mutations in the B2m and IFNγ pathways (Gao et al., 2016; Zaretsky et al., 2016), and with recent genome-wide CRISPR screening data (Patel et al., 2017).”
From Protein Barcodes Enable High-Dimensional Single-Cell CRISPR Screens (2018) · cites this paper as Zaretsky et al., 2016
Mutations in IFNGR1 and JAK, part of IFNγ signaling, have been found in patients who developed resistance to checkpoint inhibitors.
“Mutations in IFNGR1 and JAK, a component of the IFNγ signaling pathway, have been found in patients presenting resistance to checkpoint inhibitors (Gao et al., 2016; Zaretsky et al., 2016).”
From Protein Barcodes Enable High-Dimensional Single-Cell CRISPR Screens (2018) · cites this paper as Zaretsky et al., 2016
Tumor cells may evade immune recognition by downregulating tumor antigens or MHC class I.
“Tumor cells may evade immune recognition directly by downregulating features that make them vulnerable such as tumor antigens or MHC class I (4–6).”
From Anti-PD-1 and Anti-CTLA-4 Therapies in Cancer: Mechanisms of Action, Efficacy, and Limitations (2018) · cites this paper as [6]
Tumors in anti-PD-1-treated patients who initially responded then relapsed showed mutations causing loss of MHC class I surface expression or IFN-γ response elements.
“Tumors in patients treated with anti-PD-1 who initially responded and then relapsed showed mutations that caused a subsequent loss in MHC class I surface expression (to avoid cytotoxic T cell recognition) or in IFN-γ response elements (6).”
From Anti-PD-1 and Anti-CTLA-4 Therapies in Cancer: Mechanisms of Action, Efficacy, and Limitations (2018) · cites this paper as [6]
Tumor cells from patients refractory to anti-PD-1 treatment acquired mutations making them less susceptible to T cell-mediated killing via loss of IFN-γ response elements or MHC class I.
“Tumor cells from patients refractory to anti-PD-1 treatment, for example, were recently shown to have acquired mutations making them less susceptible to T cell-mediated killing via loss of IFN-γ response elements or MHC class I (6).”
From Anti-PD-1 and Anti-CTLA-4 Therapies in Cancer: Mechanisms of Action, Efficacy, and Limitations (2018) · cites this paper as [6]
Melanoma patients with genomic defects in IFN-gamma pathway genes did not respond to anti-CTLA4.
“Consistent with the preclinical data, patients with melanoma harboring genomic defects in IFNγ pathway genes did not respond to anti-CTLA4 (160).”
From The Next Decade of Immune Checkpoint Therapy (2021) · cites this paper as [160]
In the same study, another relapsed patient had a frameshift deletion of B2M, disrupting MHC I trafficking and rendering tumor cells invisible to cytotoxic CD8+ T cells.
“In the same study, tumor cells in another patient demonstrating relapse contained a frameshift deletion of β 2 -microglobulin (B2M), disrupting MHC I trafficking to the cell surface and thereby rendering the tumor cells invisible to cytotoxic CD8 + T cells (110).”
From Immune Checkpoint Inhibitors for the Treatment of Cancer: Clinical Impact and Mechanisms of Response and Resistance (2021) · cites this paper as [110]
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- Authors
- Zaretsky, J. M., Garcia-Diaz, A., Shin, D. S., Escuin-Ordinas, H., Hugo, W., Hu-Lieskovan, S., Torrejon, D. Y., Abril-Rodriguez, G., Sandoval, S., Barthly, L., Saco, J., Homet Moreno, B., Mezzadra, R., Chmielowski, B., Ruchalski, K., Shintaku, I. P., Sanchez, P. J., Puig-Saus, C., Cherry, G., Seja, E., Kong, X., Pang, J., Berent-Maoz, B., Comin-Anduix, B., Graeber, T. G., Tumeh, P. C., Schumacher, T. N. M., Lo, R. S., & Ribas, A.
- Affiliations
- University of California, Los Angeles (US)
- ORCID
- Venue
- New England Journal of Medicine
- Publisher
- Massachusetts Medical Society
- Published
- 2016-09
- Volume
- 375
- Issue
- 9
- Pages
- 819-829
- ISSN
- 0028-4793 (ISSN-L)
- 1533-4406
- PMC
- PMC5007206
- OpenAlex
- W2465860350
- Cited by
- 3,237
- References
- 39
- Citations by year
- 2026: 272 · 2025: 239 · 2024: 248 · 2023: 317 · 2022: 351 · 2021: 413 · 2020: 381 · 2019: 305 · 2018: 338 · 2017: 323 · 2016: 45 · 2012: 1
- FWCI
- 181.77
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- New England Journal of Medicine (publishedVersion)
- PubMed (publishedVersion)
- PubMed Central (acceptedVersion)
- eScholarship (California Digital Library) (submittedVersion)
- Funders
- American Association for Cancer Research (5T32AR058921-05, 5T32CA009120-39, SU2C-AACR-DT1012, 5T32CA009297-30)
- Cancer Research Institute (SU2C-AACR-DT1012)
- American Skin Association
- Melanoma Research Alliance (SU2C-AACR-DT1012, 20120279)
- Entertainment Industry Foundation
- University of Chicago
- Tower Cancer Research Foundation (5T32CA009297-30, 5T32CA009120-39, 5T32AR058921-05)
- Hope Foundation
- National Institutes of Health (UL1TR000124, 5t32ar058921-04, SU2C-AACR-DT1012, CA199090, CA197633, UL1TR001881)
- Stand Up To Cancer (5T32CA009297-30, SU2C-AACR-DT1012), 5T32AR058921-05, 5T32CA009120-39)
- National Cancer Institute (P01CA168585, U54CA199090, R01CA170689, T32CA009297, T32CA009120, R35CA197633, P30CA016042)
- National Institute of General Medical Sciences (GM-08042, T32GM008042)
- National Institute of Arthritis and Musculoskeletal and Skin Diseases (5T32AR058921-05, T32-AR058921)
- National Center for Advancing Translational Sciences
- Topics
- Health Sciences › Medicine › Oncology › Cancer Immunotherapy and Biomarkers
- Health Sciences › Medicine › Oncology › Cutaneous Melanoma Detection and Management
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Melanoma and MAPK Pathways
- Keywords
- acquired resistance, anti-PD-1 therapy, melanoma, pembrolizumab, JAK1 mutations, JAK2 mutation, beta2-microglobulin, interferon-gamma signaling, MHC class I loss, clonal selection, immune evasion, tumor recurrence, immunotherapy resistance
- MeSH terms
- Antineoplastic Agents, beta 2-Microglobulin, Biopsy, Genes, MHC Class I, Humans, Immunotherapy, Interferon-gamma, Melanoma, Mutation, Recurrence, Signal Transduction, Gene Expression Regulation, Neoplastic, Sequence Analysis, DNA, Drug Resistance, Neoplasm, Janus Kinase 1, Janus Kinase 2, Exome, Programmed Cell Death 1 Receptor, Antibodies, Monoclonal, Humanized
About these checks
Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.
Statistics and arithmetic are recomputed, not judged.
Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.
What counts as a claim ›How we measure confidence ›How we check this ›
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