Germline modifiers of the tumor immune microenvironment implicate drivers of cancer risk and immunotherapy response
Meghana S. Pagadala, Timothy J. Sears, Victoria H. Wu, Eva Pérez‐Guijarro, Hyo Kim, A. Castro, James V. Talwar, Cristian González-Colín, Steven Cao, Benjamin Joachim 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
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.