Germline Features Associated with Immune Infiltration in Solid Tumors
Sahar Shahamatdar,
Meng Xiao He,
Matthew A. Reyna,
Alexander Gusev,
Saud H. AlDubayan,
Eliezer M. Van Allen,
Sohini Ramachandran
Affiliations
Sahar Shahamatdar
Center for Computational Molecular Biology, Brown University, Providence, RI 02912, USA; Department of Ecology and Evolutionary Biology, Brown University, Providence, RI 02912, USA
Meng Xiao He
Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA 02215, USA; Broad Institute of Harvard and MIT, Cambridge, MA 02142, USA; Harvard Graduate Program in Biophysics, Boston, MA 02115, USA
Matthew A. Reyna
Department of Biomedical Informatics, Emory University, Atlanta, GA 30322, USA; Department of Computer Science, Princeton University, Princeton, NJ 08544, USA
Alexander Gusev
Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA 02215, USA; Broad Institute of Harvard and MIT, Cambridge, MA 02142, USA; Division of Genetics, Brigham and Women’s Hospital, Boston, MA 02115, USA
Saud H. AlDubayan
Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA 02215, USA; Broad Institute of Harvard and MIT, Cambridge, MA 02142, USA; Division of Genetics, Brigham and Women’s Hospital, Boston, MA 02115, USA
Eliezer M. Van Allen
Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA 02215, USA; Broad Institute of Harvard and MIT, Cambridge, MA 02142, USA; Corresponding author
Sohini Ramachandran
Center for Computational Molecular Biology, Brown University, Providence, RI 02912, USA; Department of Ecology and Evolutionary Biology, Brown University, Providence, RI 02912, USA; Corresponding author
Summary: The immune composition of the tumor microenvironment influences response and resistance to immunotherapies. While numerous studies have identified somatic correlates of immune infiltration, germline features that associate with immune infiltrates in cancers remain incompletely characterized. We analyze seven million autosomal germline variants in the TCGA cohort and test for association with established immune-related phenotypes that describe the tumor immune microenvironment. We identify one SNP associated with the amount of infiltrating follicular helper T cells; 23 candidate genes, some of which are involved in cytokine-mediated signaling and others containing cancer-risk SNPs; and networks with genes that are part of the DNA repair and transcription elongation pathways. In addition, we find a positive association between polygenic risk for rheumatoid arthritis and amount of infiltrating CD8+ T cells. Overall, we identify multiple germline genetic features associated with tumor-immune phenotypes and develop a framework for probing inherited features that contribute to differences in immune infiltration. : The role of inherited variants in influencing the immune composition of the tumor microenvironment is not fully characterized. Shahamatdar et al. identify germline variants, genes, and pathways associated with immune infiltration phenotypes in cancer, which may offer insights into determinants of response to immunotherapy. Keywords: somatic, germline, immune, SNPs, gwas, cancer, immunotherapy
