Germline modifiers of the tumor immune microenvironment implicate drivers of cancer risk and immunotherapy response
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Published:2023-05-12
Issue:1
Volume:14
Page:
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ISSN:2041-1723
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Container-title:Nature Communications
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language:en
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Short-container-title:Nat Commun
Author:
Pagadala MeghanaORCID, Sears Timothy J.ORCID, Wu Victoria H., Pérez-Guijarro EvaORCID, Kim Hyo, Castro Andrea, Talwar James V.ORCID, Gonzalez-Colin Cristian, Cao Steven, Schmiedel Benjamin J.ORCID, Goudarzi Shervin, Kirani DivyaORCID, Au JessicaORCID, Zhang TongwuORCID, Landi TeresaORCID, Salem Rany M.ORCID, Morris Gerald P.ORCID, Harismendy Olivier, Patel Sandip Pravin, Alexandrov Ludmil B., Mesirov Jill P., Zanetti Maurizio, Day Chi-PingORCID, Fan Chun ChiehORCID, Thompson Wesley K., Merlino Glenn, Gutkind J. Silvio, Vijayanand PanduranganORCID, Carter HannahORCID
Abstract
AbstractWith 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.
Funder
U.S. Department of Health & Human Services | NIH | National Cancer Institute The Mark Foundation for Cancer Research 18-022-ELA U.S. Department of Health & Human Services | National Institutes of Health
Publisher
Springer Science and Business Media LLC
Subject
General Physics and Astronomy,General Biochemistry, Genetics and Molecular Biology,General Chemistry,Multidisciplinary
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