Acquired resistance to programmed death 1 (PD-1) blockade immunotherapy of patients with melanoma may be associated with defects in the pathways that are involved in interferon-receptor signaling and in antigen presentation, according to a study published in The New England Journal of Medicine.1

Researchers analyzed biopsy samples from paired baseline and relapsing lesions in 4 patients with metastatic melanoma to examine the mechanisms of immune-resistance in cancer progression.

The patients had an initial objective tumor regression in response to anti-PD-1 therapy with pembrolizumab, followed by disease progression months or years later.

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Upon whole-exome sequencing, the researchers detected clonal selection and outgrowth of the resistant tumors. Two of the 4 patients had resistance-associated loss-of-function mutations in the genes that encoded interferon-receptor-associated Janus kinase 1 (JAK1) or Janus kinase 2 (JAK2).

A truncating mutation in the gene encoding the antigen-presenting protein beta-2-microglobulin (B2M) was identified in a third patient.

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The JAK1 and JAK2 truncating mutations resulted in a lack of response to interferon gamma, which included insensitivity to its antiproliferative effects on cancer cells. The B2M truncating mutation led to a loss of surface expression of major histocompatibility complex class I.


  1. Zaretsky JM, Garcia-Diaz A, Shin DS, et al. Mutations associated with acquired resistance to PD-1 blockade in melanoma. 13 Jul 2016. N Engl J Med. doi: 10.1056/NEJMoa1604958 [Epub ahead of print]