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Interfering with interferon Gamma: The mechanisms behind acquired resistance to PD-1 inhibitors for melanoma

DII small banner By Warren R. Heymann, MD
Sept. 4, 2016

Astounding major advances in targeted therapies for melanoma, most notably by PD-1 blockade, have given hope and life to patients with metastatic melanoma. Approximately 30 % of advanced melanoma patients experience tumor responses from checkpoint blockade monotherapy, with better clinical responses seen with the combination of anti-PD-1 and anti-CTLA-4 antibodies (1).

Despite the durable remission in some patients, unfortunately resistance to PD-1 blockade may develop. Understanding the pathomechanism(s) of such resistance is crucial to be able research how to obviate these changes.
Zaretsky et al 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. 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. The authors concluded that 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 (2).
In a Lancet news article summarizing this research, Zaretsky noted that JAK1 and JAK2 are crucial for mediating interferon-related signaling. Relapsed tumors that developed mutations in JAK1 and JAK2 would therefore become resistant to treatment. Regarding the mutation in B2M, “without this protein, tumour cells no longer present antigens to T cells. So whereas mutations in JAK1 and JAK2 suggest that the tumour is insensitive to T cells inhibition, a mutation in B2M means the T-cells cannot recognise the tumour in the first place.” (3)

The potential impact of deciphering resistance pathways of melanoma (and other malignancies) cannot be overstated. Inevitably, maneuvers that can either prevent these mutations, or salvage patients from their ill effects, will have a profound impact on longevity.

1. Ma, W. Current status and perspectives in translational biomarker research for PD-1/PD-L1 immune checkpoint blockade therapy. J Hematol Oncol 2016; 9:47.
2. Zaretsky JM, et al. Mutations associated with acquired resistance to PD-1 blockade in melanoma. N Engl J Med 2016; 375: 819-29.
3. Burki TK. Resistance to PD-1 blockade in melanoma. Lancet Oncol 2016 July 21 [Epub ahead of print]

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