Nature Communications (May 2023)
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,
- Hannah Carter
Affiliations
- Meghana Pagadala
- Biomedical Sciences Program, University of California San Diego
- Timothy J. Sears
- Bioinformatics and Systems Biology Program, University of California San Diego
- Victoria H. Wu
- Department of Pharmacology, UCSD Moores Cancer Center
- Eva Pérez-Guijarro
- Laboratory of Cancer Biology and Genetics, National Cancer Institute, National Institutes of Health (NIH)
- Hyo Kim
- Undergraduate Bioengineering Program, Jacobs School of Engineering, University of California San Diego
- Andrea Castro
- Bioinformatics and Systems Biology Program, University of California San Diego
- James V. Talwar
- Bioinformatics and Systems Biology Program, University of California San Diego
- Cristian Gonzalez-Colin
- La Jolla Institute for Immunology
- Steven Cao
- Division of Epidemiology, Herbert Wertheim School of Public Health and Human Longevity Science, University of California San Diego
- Benjamin J. Schmiedel
- La Jolla Institute for Immunology
- Shervin Goudarzi
- Canyon Crest Academy
- Divya Kirani
- Undergraduate Biology and Bioinformatics Program, University of California San Diego
- Jessica Au
- Bioinformatics and Systems Biology Program, University of California San Diego
- Tongwu Zhang
- Division of Cancer Epidemiology and Genetics, National Cancer Institute, National Institutes of Health (NIH)
- Teresa Landi
- Division of Cancer Epidemiology and Genetics, National Cancer Institute, National Institutes of Health (NIH)
- Rany M. Salem
- Division of Epidemiology, Herbert Wertheim School of Public Health and Human Longevity Science, University of California San Diego
- Gerald P. Morris
- Department of Pathology, University of California San Diego
- Olivier Harismendy
- Bioinformatics and Systems Biology Program, University of California San Diego
- Sandip Pravin Patel
- Center for Personalized Cancer Therapy, Division of Hematology and Oncology, UC San Diego Moores Cancer Center
- Ludmil B. Alexandrov
- Department of Cellular and Molecular Medicine, University of California San Diego
- Jill P. Mesirov
- Moores Cancer Center, University of California San Diego
- Maurizio Zanetti
- Moores Cancer Center, University of California San Diego
- Chi-Ping Day
- Laboratory of Cancer Biology and Genetics, National Cancer Institute, National Institutes of Health (NIH)
- Chun Chieh Fan
- Center for Population Neuroscience and Genetics, Laureate Institute for Brain Research
- Wesley K. Thompson
- Division of Biostatistics, Herbert Wertheim School of Public Health and Human Longevity Science, University of California San Diego
- Glenn Merlino
- Laboratory of Cancer Biology and Genetics, National Cancer Institute, National Institutes of Health (NIH)
- J. Silvio Gutkind
- Department of Pharmacology, UCSD Moores Cancer Center
- Pandurangan Vijayanand
- La Jolla Institute for Immunology
- Hannah Carter
- Moores Cancer Center, University of California San Diego
- DOI
- https://doi.org/10.1038/s41467-023-38271-5
- Journal volume & issue
-
Vol. 14,
no. 1
pp. 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.
