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

doi:10.1016/j.celrep.2020.02.039

Germline Features Associated with Immune Infiltration in Solid Tumors

Cell Rep. 2020 Mar 3;30(9):2900-2908.e4. doi: 10.1016/j.celrep.2020.02.039.

Authors

Sahar Shahamatdar¹, Meng Xiao He², Matthew A Reyna³, Alexander Gusev⁴, Saud H AlDubayan⁴, Eliezer M Van Allen⁵, Sohini Ramachandran⁶

Affiliations

¹ Center for Computational Molecular Biology, Brown University, Providence, RI 02912, USA; Department of Ecology and Evolutionary Biology, Brown University, Providence, RI 02912, USA.
² 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.
³ Department of Biomedical Informatics, Emory University, Atlanta, GA 30322, USA; Department of Computer Science, Princeton University, Princeton, NJ 08544, USA.
⁴ 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.
⁵ Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA 02215, USA; Broad Institute of Harvard and MIT, Cambridge, MA 02142, USA. Electronic address: [email protected].
⁶ Center for Computational Molecular Biology, Brown University, Providence, RI 02912, USA; Department of Ecology and Evolutionary Biology, Brown University, Providence, RI 02912, USA. Electronic address: [email protected].

Abstract

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.

Keywords: SNPs; cancer; germline; gwas; immune; immunotherapy; somatic.

Publication types

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

MeSH terms

Autoimmune Diseases / immunology
DNA Repair / genetics
Genetic Predisposition to Disease
Genome-Wide Association Study
Germ Cells / metabolism*
Humans
Leukocytes / metabolism
Lymphocytes, Tumor-Infiltrating / immunology*
Multifactorial Inheritance
Neoplasms / genetics*
Neoplasms / immunology*
Phenotype
Polymorphism, Single Nucleotide / genetics
Risk Factors
T-Lymphocytes, Helper-Inducer / immunology
Transcription, Genetic

Abstract

Publication types

MeSH terms

Grants and funding