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 Adalsteinsson & 11 others Gad 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

Research output: Contribution to journalArticle

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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

Fingerprint

beta 2-Microglobulin
Antigen Presentation
antigens
deactivation
therapy
Antigens
Melanoma
Loss of Heterozygosity
deletion
transponders
Histocompatibility Antigens Class I
Biopsy
Therapeutics
mutations
Point Mutation
Tumors
tumors
Survival
Neoplasms

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., ... 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

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

In: Nature Communications, Vol. 8, No. 1, 1136, 01.12.2017.

Research output: Contribution to journalArticle

Sade-Feldman, M, Jiao, YJ, Chen, JH, Rooney, MS, Barzily-Rokni, M, Eliane, JP, Bjorgaard, SL, Hammond, MR, Vitzthum, H, Blackmon, SM, Frederick, DT, Hazar-Rethinam, M, Nadres, BA, Van Seventer, EE, Shukla, SA, Yizhak, K, Ray, JP, Rosebrock, D, Livitz, D, Adalsteinsson, V, Getz, G, Duncan, LM, Li, B, Corcoran, RB, Lawrence, DP, Stemmer-Rachamimov, A, Boland, GM, Landau, DA, Flaherty, KT, Sullivan, RJ & Hacohen, N 2017, 'Resistance to checkpoint blockade therapy through inactivation of antigen presentation', Nature Communications, vol. 8, no. 1, 1136. https://doi.org/10.1038/s41467-017-01062-w
Sade-Feldman M, Jiao YJ, Chen JH, Rooney MS, Barzily-Rokni M, Eliane JP et al. Resistance to checkpoint blockade therapy through inactivation of antigen presentation. Nature Communications. 2017 Dec 1;8(1). 1136. https://doi.org/10.1038/s41467-017-01062-w
Sade-Feldman, Moshe ; Jiao, Yunxin J. ; Chen, Jonathan H. ; Rooney, Michael S. ; Barzily-Rokni, Michal ; Eliane, Jean Pierre ; Bjorgaard, Stacey L. ; Hammond, Marc R. ; Vitzthum, Hans ; Blackmon, Shauna M. ; Frederick, Dennie T. ; Hazar-Rethinam, Mehlika ; Nadres, Brandon A. ; Van Seventer, Emily E. ; Shukla, Sachet A. ; Yizhak, Keren ; Ray, John P. ; Rosebrock, Daniel ; Livitz, Dimitri ; Adalsteinsson, Viktor ; Getz, Gad ; Duncan, Lyn M. ; Li, Bo ; Corcoran, Ryan B. ; Lawrence, Donald P. ; Stemmer-Rachamimov, Anat ; Boland, Genevieve M. ; Landau, Dan A. ; Flaherty, Keith T. ; Sullivan, Ryan J. ; Hacohen, Nir. / Resistance to checkpoint blockade therapy through inactivation of antigen presentation. In: Nature Communications. 2017 ; Vol. 8, No. 1.
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