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Identification of Mediators of T-cell Receptor Signaling via the Screening of Chemical Inhibitor Libraries
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Resistance to checkpoint blockade therapy through inactivation of antigen presentation

Moshe Sade-Feldman1,2, Yunxin J Jiao2,3, Jonathan H Chen2,4

  • 1Department of Medicine, Massachusetts General Hospital Cancer Center, Boston, MA, 02114, USA.

Nature Communications
|October 27, 2017
PubMed

Insights

Loss of beta-2-microglobulin (B2M) in melanoma tumors is a key mechanism of resistance to immune checkpoint blockade therapies. This finding helps explain treatment failure and may guide future therapeutic strategies.

Area of Science:

  • Immunology
  • Oncology
  • Genetics

Background:

  • Immune checkpoint blockade (CPB) therapies offer prolonged responses in metastatic melanoma.
  • Mechanisms of primary and acquired resistance to CPB are not fully understood.

Purpose of the Study:

  • To investigate the role of beta-2-microglobulin (B2M) mutations and loss of heterozygosity (LOH) in melanoma resistance to CPB therapies.

Main Methods:

  • Analysis of longitudinal tumor biopsies from 17 metastatic melanoma patients treated with CPB.
  • Validation in two independent cohorts of melanoma patients treated with anti-CTLA4 and anti-PD1.
  • Assessment of B2M mutations, deletions, and LOH.

Main Results:

  • B2M mutations, deletions, or LOH were observed in 29.4% of patients with progressing disease.
  • B2M LOH was threefold enriched in non-responders (~30%) compared to responders (~10%) across cohorts.
  • Loss of both B2M copies was exclusively found in non-responders, correlating with poorer overall survival.

Conclusions:

  • B2M loss is a significant mechanism of primary and acquired resistance to anti-CTLA4 and anti-PD1 therapies in melanoma.
  • Identifying B2M alterations can predict treatment response and inform therapeutic strategies.

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