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; 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

doi:10.1038/s41467-017-01062-w

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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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 language	English (US)
Article number	1136
Journal	Nature communications
Volume	8
Issue number	1
DOIs	https://doi.org/10.1038/s41467-017-01062-w
State	Published - Dec 1 2017

ASJC Scopus subject areas

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

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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

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

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title = "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.",

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

note = "Funding Information: We thank the Genomics Platform of the Broad Institute of Harvard and MIT for the whole exome and RNA sequencing performed in this study. The research was supported by grants from Melanoma Research Alliance (Sullivan), Broad Next-10 (Hacohen), Cancer Research Institute (Clinic and Laboratory Integration Program, Hacohen), Adelson Medical Research Foundation (Flaherty; Sullivan, Hacohen), NIH/NCI (1R01CA208756, Hacohen), and NIH/NHGRI (5U54HG003067; PIs: Stacey Gabriel, Eric S. Lander). We also thank the following grants for their support: Wellcome Fund Career Award for Medical Scientists (Landau), Stand Up to Cancer Innovative Research Grant (Landau), NIH Big Data to Knowledge initiative (1K01ES025431-0, Landau), Institute for Medical Research Israel-Canada (Sade-Feldman), Tosteson & Fund for Medical Discovery fellowships (Sade-Feldman), and National Science Foundation Graduate Research Fellowship (Jiao). Publisher Copyright: {\textcopyright} 2017 The Author(s).",

year = "2017",

month = dec,

day = "1",

doi = "10.1038/s41467-017-01062-w",

language = "English (US)",

volume = "8",

journal = "Nature Communications",

issn = "2041-1723",

publisher = "Nature Publishing Group",

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T1 - Resistance to checkpoint blockade therapy through inactivation of antigen presentation

AU - Sade-Feldman, Moshe

AU - Jiao, Yunxin J.

AU - Chen, Jonathan H.

AU - Rooney, Michael S.

AU - Barzily-Rokni, Michal

AU - Eliane, Jean Pierre

AU - Bjorgaard, Stacey L.

AU - Hammond, Marc R.

AU - Vitzthum, Hans

AU - Blackmon, Shauna M.

AU - Frederick, Dennie T.

AU - Hazar-Rethinam, Mehlika

AU - Nadres, Brandon A.

AU - Van Seventer, Emily E.

AU - Shukla, Sachet A.

AU - Yizhak, Keren

AU - Ray, John P.

AU - Rosebrock, Daniel

AU - Livitz, Dimitri

AU - Adalsteinsson, Viktor

AU - Getz, Gad

AU - Duncan, Lyn M.

AU - Li, Bo

AU - Corcoran, Ryan B.

AU - Lawrence, Donald P.

AU - Stemmer-Rachamimov, Anat

AU - Boland, Genevieve M.

AU - Landau, Dan A.

AU - Flaherty, Keith T.

AU - Sullivan, Ryan J.

AU - Hacohen, Nir

N1 - Funding Information: We thank the Genomics Platform of the Broad Institute of Harvard and MIT for the whole exome and RNA sequencing performed in this study. The research was supported by grants from Melanoma Research Alliance (Sullivan), Broad Next-10 (Hacohen), Cancer Research Institute (Clinic and Laboratory Integration Program, Hacohen), Adelson Medical Research Foundation (Flaherty; Sullivan, Hacohen), NIH/NCI (1R01CA208756, Hacohen), and NIH/NHGRI (5U54HG003067; PIs: Stacey Gabriel, Eric S. Lander). We also thank the following grants for their support: Wellcome Fund Career Award for Medical Scientists (Landau), Stand Up to Cancer Innovative Research Grant (Landau), NIH Big Data to Knowledge initiative (1K01ES025431-0, Landau), Institute for Medical Research Israel-Canada (Sade-Feldman), Tosteson & Fund for Medical Discovery fellowships (Sade-Feldman), and National Science Foundation Graduate Research Fellowship (Jiao). Publisher Copyright: © 2017 The Author(s).

PY - 2017/12/1

Y1 - 2017/12/1

N2 - 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.

AB - 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.

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Resistance to checkpoint blockade therapy through inactivation of antigen presentation

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