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

被引：0
作者：
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
Hannah Carter
机构：
[1] University of California San Diego,Biomedical Sciences Program
[2] University of California San Diego,Bioinformatics and Systems Biology Program
[3] UCSD Moores Cancer Center,Department of Pharmacology
[4] National Cancer Institute,Laboratory of Cancer Biology and Genetics
[5] National Institutes of Health (NIH),Undergraduate Bioengineering Program, Jacobs School of Engineering
[6] University of California San Diego,Division of Epidemiology, Herbert Wertheim School of Public Health and Human Longevity Science
[7] La Jolla Institute for Immunology,Undergraduate Biology and Bioinformatics Program
[8] University of California San Diego,Division of Cancer Epidemiology and Genetics
[9] Canyon Crest Academy,Department of Pathology
[10] University of California San Diego,Division of Biomedical Informatics, Department of Medicine
[11] National Cancer Institute,Center for Personalized Cancer Therapy, Division of Hematology and Oncology
[12] National Institutes of Health (NIH),Department of Cellular and Molecular Medicine
[13] University of California San Diego,Department of Bioengineering
[14] University of California San Diego School of Medicine,Moores Cancer Center
[15] UC San Diego Moores Cancer Center,Department of Medicine, Division of Medical Genetics
[16] University of California San Diego,The Laboratory of Immunology and Department of Medicine
[17] University of California San Diego,Center for Population Neuroscience and Genetics
[18] University of California San Diego,Department of Radiology
[19] University of California San Diego,Division of Biostatistics, Herbert Wertheim School of Public Health and Human Longevity Science
[20] University of California San Diego,undefined
[21] Laureate Institute for Brain Research,undefined
[22] University of California San Diego,undefined
[23] University of California San Diego,undefined
来源：
Nature Communications | / 14卷
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摘要：
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.
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