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

doi:10.1038/s41467-023-38271-5

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

Nat Commun. 2023 May 12;14(1):2744. doi: 10.1038/s41467-023-38271-5.

Authors

Meghana Pagadala¹, Timothy J Sears², Victoria H Wu³, Eva Pérez-Guijarro⁴, Hyo Kim⁵, Andrea Castro², James V Talwar², Cristian Gonzalez-Colin⁶, Steven Cao⁷, Benjamin J Schmiedel⁶, Shervin Goudarzi⁸, Divya Kirani⁹, Jessica Au², Tongwu Zhang¹⁰, Teresa Landi¹⁰, Rany M Salem⁷, Gerald P Morris¹¹, Olivier Harismendy^{2

12}, Sandip Pravin Patel¹³, Ludmil B Alexandrov^{14

15}, Jill P Mesirov^{16

17}, Maurizio Zanetti^{16

18}, Chi-Ping Day⁴, Chun Chieh Fan^{19

20}, Wesley K Thompson²¹, Glenn Merlino⁴, J Silvio Gutkind³, Pandurangan Vijayanand⁶, Hannah Carter^{22

23}

Affiliations

¹ Biomedical Sciences Program, University of California San Diego, La Jolla, CA, 92093, USA.
² Bioinformatics and Systems Biology Program, University of California San Diego, La Jolla, CA, 92093, USA.
³ Department of Pharmacology, UCSD Moores Cancer Center, La Jolla, CA, 92093, USA.
⁴ Laboratory of Cancer Biology and Genetics, National Cancer Institute, National Institutes of Health (NIH), Bethesda, MD, 20892, USA.
⁵ Undergraduate Bioengineering Program, Jacobs School of Engineering, University of California San Diego, La Jolla, CA, 92093, USA.
⁶ La Jolla Institute for Immunology, La Jolla, CA, 92037, USA.
⁷ Division of Epidemiology, Herbert Wertheim School of Public Health and Human Longevity Science, University of California San Diego, La Jolla, CA, 92093, USA.
⁸ Canyon Crest Academy, San Diego, CA, 92130, USA.
⁹ Undergraduate Biology and Bioinformatics Program, University of California San Diego, La Jolla, CA, 92093, USA.
¹⁰ Division of Cancer Epidemiology and Genetics, National Cancer Institute, National Institutes of Health (NIH), Bethesda, MD, 20892, USA.
¹¹ Department of Pathology, University of California San Diego, La Jolla, CA, 92093, USA.
¹² Division of Biomedical Informatics, Department of Medicine, University of California San Diego School of Medicine, La Jolla, CA, 92093, USA.
¹³ Center for Personalized Cancer Therapy, Division of Hematology and Oncology, UC San Diego Moores Cancer Center, San Diego, CA, 92037, USA.
¹⁴ Department of Cellular and Molecular Medicine, University of California San Diego, La Jolla, CA, 92093, USA.
¹⁵ Department of Bioengineering, University of California San Diego, La Jolla, CA, 92093, USA.
¹⁶ Moores Cancer Center, University of California San Diego, La Jolla, CA, 92093, USA.
¹⁷ Department of Medicine, Division of Medical Genetics, University of California San Diego, La Jolla, CA, 92093, USA.
¹⁸ The Laboratory of Immunology and Department of Medicine, University of California San Diego, La Jolla, CA, 92093, USA.
¹⁹ Center for Population Neuroscience and Genetics, Laureate Institute for Brain Research, Tulsa, OK, 74136, USA.
²⁰ Department of Radiology, University of California San Diego, La Jolla, CA, 92093, USA.
²¹ Division of Biostatistics, Herbert Wertheim School of Public Health and Human Longevity Science, University of California San Diego, La Jolla, CA, 92093, USA.
²² Moores Cancer Center, University of California San Diego, La Jolla, CA, 92093, USA. hkcarter@health.ucsd.edu.
²³ Department of Medicine, Division of Medical Genetics, University of California San Diego, La Jolla, CA, 92093, USA. hkcarter@health.ucsd.edu.

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.

Publication types

Research Support, Non-U.S. Gov't
Research Support, N.I.H., Extramural
Research Support, N.I.H., Intramural

MeSH terms

Germ Cells
Germ-Line Mutation
Immunotherapy*
Inhibition, Psychological
Macrophages
Neoplasms* / genetics
Neoplasms* / therapy
Tumor Microenvironment / genetics

Abstract

Publication types

MeSH terms

Grants and funding