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Resistance to checkpoint blockade therapy through inactivation of antigen presentation.

ABSTRACT: Treatment with immune checkpoint blockade (CPB) therapies often leads to prolonged responses in patients with metastatic melanoma, but the common mechanisms of primary and acquired resistance to these agents remain incompletely characterized and have yet to be validated in large cohorts. By analyzing longitudinal tumor biopsies from 17 metastatic melanoma patients treated with CPB therapies, we observed point mutations, deletions or loss of heterozygosity (LOH) in beta-2-microglobulin (B2M), an essential component of MHC class I antigen presentation, in 29.4% of patients with progressing disease. In two independent cohorts of melanoma patients treated with anti-CTLA4 and anti-PD1, respectively, we find that B2M LOH is enriched threefold in non-responders (~30%) compared to responders (~10%) and associated with poorer overall survival. Loss of both copies of B2M is found only in non-responders. B2M loss is likely a common mechanism of resistance to therapies targeting CTLA4 or PD1.

SUBMITTER: Sade-Feldman M 

PROVIDER: S-EPMC5656607 | biostudies-literature | 2017 Oct

REPOSITORIES: biostudies-literature

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Resistance to checkpoint blockade therapy through inactivation of antigen presentation.

Sade-Feldman Moshe M   Jiao Yunxin J YJ   Chen Jonathan H JH   Rooney Michael S MS   Barzily-Rokni Michal M   Eliane Jean-Pierre JP   Bjorgaard Stacey L SL   Hammond Marc R MR   Vitzthum Hans H   Blackmon Shauna M SM   Frederick Dennie T DT   Hazar-Rethinam Mehlika M   Nadres Brandon A BA   Van Seventer Emily E EE   Shukla Sachet A SA   Yizhak Keren K   Ray John P JP   Rosebrock Daniel D   Livitz Dimitri D   Adalsteinsson Viktor V   Getz Gad G   Duncan Lyn M LM   Li Bo B   Corcoran Ryan B RB   Lawrence Donald P DP   Stemmer-Rachamimov Anat A   Boland Genevieve M GM   Landau Dan A DA   Flaherty Keith T KT   Sullivan Ryan J RJ   Hacohen Nir N  

Nature communications 20171026 1

Treatment with immune checkpoint blockade (CPB) therapies often leads to prolonged responses in patients with metastatic melanoma, but the common mechanisms of primary and acquired resistance to these agents remain incompletely characterized and have yet to be validated in large cohorts. By analyzing longitudinal tumor biopsies from 17 metastatic melanoma patients treated with CPB therapies, we observed point mutations, deletions or loss of heterozygosity (LOH) in beta-2-microglobulin (B2M), an  ...[more]

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