TY - JOUR
T1 - Stroma remodeling and reduced cell division define durable response to PD-1 blockade in melanoma
AU - Galvani, Elena
AU - Mundra, Piyushkumar A.
AU - Valpione, Sara
AU - Garcia-Martinez, Pablo
AU - Smith, Matthew
AU - Greenall, Jonathan
AU - Thakur, Rohit
AU - Helmink, Beth
AU - Andrews, Miles C.
AU - Boon, Louis
AU - Chester, Christopher
AU - Gremel, Gabriela
AU - Hogan, Kate
AU - Mandal, Amit
AU - Zeng, Kang
AU - Banyard, Antonia
AU - Ashton, Garry
AU - Cook, Martin
AU - Lorigan, Paul
AU - Wargo, Jennifer A.
AU - Dhomen, Nathalie
AU - Marais, Richard
N1 - Funding Information:
R.M. is supported by Wellcome Trust (100282/Z/12/Z), European Research Council Advanced Grant (ERC-ADG-2014 671262), Cancer Research UK (A27412 and A22902). B.H. is supported by National Institutes of Health T32 CA 009599 and the MD Anderson Cancer Center support grant (P30 CA016672). M.C.A. is supported by a National Health and Medical Research Council of Australia CJ Martin Early Career Fellowship (#1148680). J.A.W. is supported by the NIH (1 R01 CA219896-01A1), U.S.-Israel Binational Science Foundation (201332), the Melanoma Research Alliance (4022024), American Association for Cancer Research Stand Up To Cancer (SU2C-AACR-IRG-19-17), Department of Defense (W81XWH-16-1-0121), MD Anderson Cancer Center Multidisciplinary Research Program Grant, Andrew Sabin Family Fellows Program, and MD Anderson Cancer Center’s Melanoma Moon Shots Program. J.A.W. is a member of the Parker Institute for Cancer Immunotherapy at MD Anderson Cancer Center.
Publisher Copyright:
© 2020, The Author(s).
PY - 2020/12/1
Y1 - 2020/12/1
N2 - Although immune checkpoint inhibitors (ICIs) have achieved unprecedented results in melanoma, the biological features of the durable responses initiated by these drugs remain unknown. Here we show the genetic and phenotypic changes induced by treatment with programmed cell death-1 (PD-1) blockade in a genetically engineered mouse model of melanoma driven by oncogenic BRAF. In this controlled system anti-PD-1 treatment yields responses in ~35% of the tumors, and prolongs survival in ~27% of the animals. We identify increased stroma remodeling and reduced expression of proliferation markers as features associated with prolonged response. These traits are corroborated in two independent early on-treatment anti-PD-1 melanoma patient cohorts. These insights into the biological responses of tumors to ICI provide a strategy for identification of durable response early during the course of treatment and could improve patient stratification for checkpoint inhibitory drugs.
AB - Although immune checkpoint inhibitors (ICIs) have achieved unprecedented results in melanoma, the biological features of the durable responses initiated by these drugs remain unknown. Here we show the genetic and phenotypic changes induced by treatment with programmed cell death-1 (PD-1) blockade in a genetically engineered mouse model of melanoma driven by oncogenic BRAF. In this controlled system anti-PD-1 treatment yields responses in ~35% of the tumors, and prolongs survival in ~27% of the animals. We identify increased stroma remodeling and reduced expression of proliferation markers as features associated with prolonged response. These traits are corroborated in two independent early on-treatment anti-PD-1 melanoma patient cohorts. These insights into the biological responses of tumors to ICI provide a strategy for identification of durable response early during the course of treatment and could improve patient stratification for checkpoint inhibitory drugs.
UR - http://www.scopus.com/inward/record.url?scp=85079335722&partnerID=8YFLogxK
U2 - 10.1038/s41467-020-14632-2
DO - 10.1038/s41467-020-14632-2
M3 - Article
C2 - 32051401
AN - SCOPUS:85079335722
SN - 2041-1723
VL - 11
JO - Nature Communications
JF - Nature Communications
IS - 1
M1 - 853
ER -