Acquired Resistance to PD-1 Blockade in Melanoma

Mutations associated with mechanisms of immune-resistant cancer progression

Approximately 75% of objective responses to anti-PD-1 therapy in patients with melanoma are durable, lasting for years, but delayed relapses have been noted. Mechanisms of immune escape in this context are unknown. In a study, published online on 20 July 2016 in The New England Journal of Medicine, acquired resistance to PD-1 blockade immunotherapy in patients with melanoma was associated with defects in the pathways involved in interferon-receptor signalling and in antigen presentation.

With the approval of PD-1 checkpoint-blockade agents for the treatment of patients with melanoma, lung and other type of cancers, it is anticipated that late relapses will increase. Understanding the molecular mechanisms of acquired resistance may open options for the rational design of salvage combination therapies or preventive interventions and may guide mechanistic biomarker studies for the selection of patients who are unlikely to benefit from therapy.

In a study background, the authors wrote that approximately 25% of patients with melanoma who achieved an objective response to PD-1 blockade therapy in a recent study had disease progression at a median follow-up of 21 months. Previous studies involving humans examined the loss of beta-2-microglobulin as a mechanism of acquired resistance to several forms of cancer immunotherapy. In preclinical models, defects in the interferon signalling pathway have been proposed as a potential mechanism of insensitivity to immunotherapy.

In the current study, the authors assessed the effect of anti–PD-1 therapy on cancer genomic evolution, including acquired mutations in the genes affecting the interferon pathway and antigen-presentation pathway, in an effort to determine genetic mechanisms of acquired resistance to PD-1 blockade therapy.

Of the 78 patients with metastatic melanoma who were treated with pembrolizumab at the University of California, Los Angeles, 42 had an objective response, of whom 15 went on to have disease progression. Four of these 15 patients met all selection criteria for the analysis of biopsy samples from paired baseline and relapsing lesions.

Whole-exome sequencing detected clonal selection and outgrowth of the acquired resistant tumours 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 anti-proliferative effects on cancer cells. The B2M truncating mutation led to loss of surface expression of major histocompatibility complex class I.

The authors concluded that nearly identical mechanism of acquisition, functional consequence, and evidence of clonal selection for JAK1 or JAK2 mutations in two independent cases with a similar clinical course of acquired resistance suggest that resistance to interferon gamma contributes to immune resistance and escape. This genetic alteration of immune resistance joins the previously described loss of B2M in decreasing immune-cell recognition of cancer cells, leading to acquired resistance to cancer immunotherapy. Additional cases should be examined to assess the generalisability of these findings.


Zaretsky JM, Garcia-Diaz A, Shin DS, et al. Mutations Associated with Acquired Resistance to PD-1 Blockade in Melanoma. NEJM 2016; Published online July 13, DOI: 10.1056/NEJMoa1604958.