Mutations Associated with Acquired Resistance to PD-1 Blockade in Melanoma
- PMID: 27433843
- PMCID: PMC5007206
- DOI: 10.1056/NEJMoa1604958
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.).
Figures
Comment in
-
Melanoma: JAK - opening the door to acquired resistance.Nat Rev Clin Oncol. 2016 Sep;13(9):528-9. doi: 10.1038/nrclinonc.2016.126. Epub 2016 Aug 2. Nat Rev Clin Oncol. 2016. PMID: 27480667 No abstract available.
-
Unmasking PD-1 Resistance by Next-Generation Sequencing.N Engl J Med. 2016 Sep 1;375(9):888-9. doi: 10.1056/NEJMe1606042. N Engl J Med. 2016. PMID: 27579640 No abstract available.
-
Uncovering first molecular mechanisms of secondary resistance against PD-1 blockade.Ann Transl Med. 2016 Dec;4(23):472. doi: 10.21037/atm.2016.11.05. Ann Transl Med. 2016. PMID: 28090528 Free PMC article. No abstract available.
-
Acquired resistance mechanisms to immunotherapy.Ann Transl Med. 2016 Dec;4(24):547. doi: 10.21037/atm.2016.12.21. Ann Transl Med. 2016. PMID: 28149908 Free PMC article. No abstract available.
-
Immunotherapy resistance: the answers lie ahead - not in front - of us.J Immunother Cancer. 2017 Feb 21;5:10. doi: 10.1186/s40425-017-0212-y. eCollection 2017. J Immunother Cancer. 2017. PMID: 28239464 Free PMC article.
Similar articles
-
Primary Resistance to PD-1 Blockade Mediated by JAK1/2 Mutations.Cancer Discov. 2017 Feb;7(2):188-201. doi: 10.1158/2159-8290.CD-16-1223. Epub 2016 Nov 30. Cancer Discov. 2017. PMID: 27903500 Free PMC article.
-
Resistance to PD-1 blockade in melanoma.Lancet Oncol. 2016 Sep;17(9):e376. doi: 10.1016/S1470-2045(16)30372-2. Epub 2016 Jul 22. Lancet Oncol. 2016. PMID: 27452143 No abstract available.
-
Mutation patterns in genes encoding interferon signaling and antigen presentation: A pan-cancer survey with implications for the use of immune checkpoint inhibitors.Genes Chromosomes Cancer. 2017 Aug;56(8):651-659. doi: 10.1002/gcc.22468. Epub 2017 May 31. Genes Chromosomes Cancer. 2017. PMID: 28466543
-
Mechanisms and strategies to overcome resistance to molecularly targeted therapy for melanoma.Cancer. 2017 Jun 1;123(S11):2118-2129. doi: 10.1002/cncr.30435. Cancer. 2017. PMID: 28543695 Review.
-
CTLA-4 and PD-1/PD-L1 blockade: new immunotherapeutic modalities with durable clinical benefit in melanoma patients.Clin Cancer Res. 2013 Oct 1;19(19):5300-9. doi: 10.1158/1078-0432.CCR-13-0143. Clin Cancer Res. 2013. PMID: 24089443 Review.
Cited by
-
Immunoediting Dynamics in Glioblastoma: Implications for Immunotherapy Approaches.Cancer Control. 2024 Jan-Dec;31:10732748241290067. doi: 10.1177/10732748241290067. Cancer Control. 2024. PMID: 39353594 Free PMC article. Review.
-
Alternative Strategies for Delivering Immunotherapeutics Targeting the PD-1/PD-L1 Immune Checkpoint in Cancer.Pharmaceutics. 2024 Sep 7;16(9):1181. doi: 10.3390/pharmaceutics16091181. Pharmaceutics. 2024. PMID: 39339217 Free PMC article. Review.
-
Immune Checkpoint Inhibitor Therapy for Metastatic Melanoma: What Should We Focus on to Improve the Clinical Outcomes?Int J Mol Sci. 2024 Sep 20;25(18):10120. doi: 10.3390/ijms251810120. Int J Mol Sci. 2024. PMID: 39337605 Free PMC article. Review.
-
Oncogenic potential of SARS-CoV-2-targeting hallmarks of cancer pathways.Cell Commun Signal. 2024 Sep 26;22(1):447. doi: 10.1186/s12964-024-01818-0. Cell Commun Signal. 2024. PMID: 39327555 Free PMC article. Review.
-
TYRP1 directed CAR T cells control tumor progression in preclinical melanoma models.Mol Ther Oncol. 2024 Aug 22;32(3):200862. doi: 10.1016/j.omton.2024.200862. eCollection 2024 Sep 19. Mol Ther Oncol. 2024. PMID: 39308793 Free PMC article.
References
-
- Atkins MB, Kunkel L, Sznol M, Rosenberg SA. High-dose recombinant interleukin-2 therapy in patients with metastatic melanoma: long-term survival update. Cancer J Sci Am. 2000;6(Suppl 1):S11–4. - PubMed
Publication types
MeSH terms
Substances
Grants and funding
- GM08042/GM/NIGMS NIH HHS/United States
- T32 GM008042/GM/NIGMS NIH HHS/United States
- 5T32CA009120-39/CA/NCI NIH HHS/United States
- UL1 TR000124/TR/NCATS NIH HHS/United States
- R35 CA197633/CA/NCI NIH HHS/United States
- U54 CA199090/CA/NCI NIH HHS/United States
- P30 CA016042/CA/NCI NIH HHS/United States
- T32 CA009120/CA/NCI NIH HHS/United States
- R01 CA170689/CA/NCI NIH HHS/United States
- 5T32CA009297-30/CA/NCI NIH HHS/United States
- T32 CA009297/CA/NCI NIH HHS/United States
- P01 CA168585/CA/NCI NIH HHS/United States
- 5T32AR058921-05/AR/NIAMS NIH HHS/United States
- UL1 TR001881/TR/NCATS NIH HHS/United States
- 1U54 CA199090/CA/NCI NIH HHS/United States
- T32 AR058921/AR/NIAMS NIH HHS/United States
LinkOut - more resources
Full Text Sources
Other Literature Sources
Medical
Research Materials
Miscellaneous