Germline modifiers of the tumor immune microenvironment implicate drivers of cancer risk and immunotherapy response

Meghana Pagadala, Timothy J. Sears, Victoria H. Wu, Eva Pérez-Guijarro, Hyo Kim, Andrea Castro, James V. Talwar, Cristian Gonzalez-Colin, Steven Cao, Benjamin J. Schmiedel, Shervin Goudarzi, Divya Kirani, Jessica Au, Tongwu Zhang, Teresa Landi, Rany M. Salem, Gerald P. Morris, Olivier Harismendy, Sandip Pravin Patel, Ludmil B. Alexandrov, Jill P. Mesirov, Maurizio Zanetti, Chi-Ping Day, Chun Chieh Fan, Wesley K. Thompson, Glenn Merlino, J. Silvio Gutkind, Pandurangan Vijayanand and Hannah Carter ()
Additional contact information
Meghana Pagadala: University of California San Diego
Timothy J. Sears: University of California San Diego
Victoria H. Wu: UCSD Moores Cancer Center
Eva Pérez-Guijarro: National Cancer Institute, National Institutes of Health (NIH)
Hyo Kim: University of California San Diego
Andrea Castro: University of California San Diego
James V. Talwar: University of California San Diego
Cristian Gonzalez-Colin: La Jolla Institute for Immunology
Steven Cao: University of California San Diego
Benjamin J. Schmiedel: La Jolla Institute for Immunology
Shervin Goudarzi: Canyon Crest Academy
Divya Kirani: University of California San Diego
Jessica Au: University of California San Diego
Tongwu Zhang: National Cancer Institute, National Institutes of Health (NIH)
Teresa Landi: National Cancer Institute, National Institutes of Health (NIH)
Rany M. Salem: University of California San Diego
Gerald P. Morris: University of California San Diego
Olivier Harismendy: University of California San Diego
Sandip Pravin Patel: UC San Diego Moores Cancer Center
Ludmil B. Alexandrov: University of California San Diego
Jill P. Mesirov: University of California San Diego
Maurizio Zanetti: University of California San Diego
Chi-Ping Day: National Cancer Institute, National Institutes of Health (NIH)
Chun Chieh Fan: Laureate Institute for Brain Research
Wesley K. Thompson: University of California San Diego
Glenn Merlino: National Cancer Institute, National Institutes of Health (NIH)
J. Silvio Gutkind: UCSD Moores Cancer Center
Pandurangan Vijayanand: La Jolla Institute for Immunology
Hannah Carter: University of California San Diego

Nature Communications, 2023, vol. 14, issue 1, 1-22

Abstract: Abstract With the continued promise of immunotherapy for treating cancer, understanding how host genetics contributes to the tumor immune microenvironment (TIME) is essential to tailoring cancer screening and treatment strategies. Here, we study 1084 eQTLs affecting the TIME found through analysis of The Cancer Genome Atlas and literature curation. These TIME eQTLs are enriched in areas of active transcription, and associate with gene expression in specific immune cell subsets, such as macrophages and dendritic cells. Polygenic score models built with TIME eQTLs reproducibly stratify cancer risk, survival and immune checkpoint blockade (ICB) response across independent cohorts. To assess whether an eQTL-informed approach could reveal potential cancer immunotherapy targets, we inhibit CTSS, a gene implicated by cancer risk and ICB response-associated polygenic models; CTSS inhibition results in slowed tumor growth and extended survival in vivo. These results validate the potential of integrating germline variation and TIME characteristics for uncovering potential targets for immunotherapy.

Date: 2023
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DOI: 10.1038/s41467-023-38271-5

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