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Friday, December 3 • 4:50pm - 5:00pm
OP 29 - Germline modifiers of the tumor immune microenvironment reveal drivers of immunotherapy response

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Germline modifiers of the tumor immune microenvironment reveal drivers of immunotherapy response

Presenting Author: Meghana Pagadala, UCSD

Victoria Wu, Moores Cancer Center
Hyo Kim, UCSD
Andrea Castro, UCSD
James Talwar, UCSD
Cristian Gonzalez-Colin, La Jolla Institute of Immunology
Steven Cao, UCSD
Benjamin Schmiedel, La Jolla Institute of Immunology
Shervin Goudarzi, Canyon Crest Academy
Divya Kirani, UCSD
Rany Salem, UCSD
Gerald Morris, UCSD
Olivier Harismendy, Moores Cancer Center
Sandip Patel, Morres Cancer Center
Jill Mesirov, UCSD
Maurizio Zanetti, Moores Cancer Center
Chi-Ping Day, National Institutes of Health
Chun Fan, UCSD
Wesley Thompon, UCSD
Glenn Merlino, National Institutes of Health
Eva Pérez-Guijarro, National Institutes of Health
J Silvio Gutkind, Moores Cancer Center
Pandurangan Vijayanand, La Jolla Institute of Immunology
Hannah Carter, UCSD

Abstract: With the continued promise of immunotherapy as an avenue for treating cancer, understanding how host genetics contributes to the tumor immune microenvironment (TIME) is essential to tailoring cancer risk screening and treatment strategies. Using genotypes from over 8,000 European individuals in The Cancer Genome Atlas and 137 heritable tumor immune phenotype components (IP components), we identified and investigated 532 TIME-SNPs. Focusing on 77 variants that were relevant to cancer risk, survival, or treatment response, we explored their potential to reveal novel targets for immunotherapy. Many variants overlapped regions with histone marks indicating active transcription, and influenced gene activities in specific immune cell subsets, such as macrophages and dendritic cells. TIME-SNPs implicated genes such as LAIR1, TREX1, CTSS, CTSW and LILRB2 were differentially expressed between responders and non-responders to immune-checkpoint blockade (ICB) in preclinical studies. Of these, LILRB2 and LAIR1 have already been identified as putative targets for immunotherapy. Here we found that inhibition of CTSS led to better tumor control and survival in murine models, alone or in combination with anti-PD-1. Collectively we show that through an integrative approach, it is possible to link host genetics to TIME characteristics, informing novel biomarkers for cancer risk and target identification in immunotherapy.

Friday December 3, 2021 4:50pm - 5:00pm MST
Ballroom Salon 1