TY - JOUR
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 - 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.
UR - http://www.scopus.com/inward/record.url?scp=85032288210&partnerID=8YFLogxK
U2 - https://doi.org/10.1038/s41467-017-01062-w
DO - https://doi.org/10.1038/s41467-017-01062-w
M3 - مقالة
SN - 2041-1723
VL - 8
JO - Nature Communications
JF - Nature Communications
IS - 1
M1 - 1136
ER -