Resistance to checkpoint blockade therapy through inactivation of antigen presentation

Moshe Sade-Feldman, Yunxin J. Jiao, Jonathan H. Chen, Michael S. Rooney, Michal Barzily-Rokni, Jean Pierre Eliane, Stacey L. Bjorgaard, Marc R. Hammond, Hans Vitzthum, Shauna M. Blackmon, Dennie T. Frederick, Mehlika Hazar-Rethinam, Brandon A. Nadres, Emily E. Van Seventer, Sachet A. Shukla, Keren Yizhak, John P. Ray, Daniel Rosebrock, Dimitri Livitz, Viktor AdalsteinssonGad Getz, Lyn M. Duncan, Bo Li, Ryan B. Corcoran, Donald P. Lawrence, Anat Stemmer-Rachamimov, Genevieve M. Boland, Dan A. Landau, Keith T. Flaherty, Ryan J. Sullivan, Nir Hacohen

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143 Scopus citations

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.

Original languageEnglish (US)
Article number1136
JournalNature Communications
Volume8
Issue number1
DOIs
StatePublished - Dec 1 2017

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ASJC Scopus subject areas

  • Chemistry(all)
  • Biochemistry, Genetics and Molecular Biology(all)
  • Physics and Astronomy(all)

Cite this

Sade-Feldman, M., Jiao, Y. J., Chen, J. H., Rooney, M. S., Barzily-Rokni, M., Eliane, J. P., Bjorgaard, S. L., Hammond, M. R., Vitzthum, H., Blackmon, S. M., Frederick, D. T., Hazar-Rethinam, M., Nadres, B. A., Van Seventer, E. E., Shukla, S. A., Yizhak, K., Ray, J. P., Rosebrock, D., Livitz, D., ... Hacohen, N. (2017). Resistance to checkpoint blockade therapy through inactivation of antigen presentation. Nature Communications, 8(1), [1136]. https://doi.org/10.1038/s41467-017-01062-w