Germline Features Associated with Immune Infiltration in Solid Tumors

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.

Figure 1.. Association Study Approach and GWAS Results

(A) Schematic showing the type and size of dataset for association studies. Association studies are conducted at three genomic scales across all 17 phenotypes. (B) Manhattan plot for GWAS meta-analysis for the T_FH cell phenotype. Positions along the chromosomes are on the x axis, and −log₁₀-transformed p values are on the y axis. Every autosome is represented, but some are unlabeled for visualization purposes. The red line indicates genome-wide significance (p < 5 × 10⁻⁸). See also Figure S1.

Figure 2.. Summary of Gene-Level Association Results

(A) Gene-level association testing identified 23 unique candidate genes. Four candidate genes contained published GWAS SNPs related to cancer traits; five candidate genes contained published GWAS SNPs related to immunity or autoimmune traits. Out of the genes with no previously known associations, the Gene Ontology (GO) term with the most members is shown. Suggestive and candidate genes annotated as casually implicated in cancer by the Cancer Gene Census are also shown. Genes are colored according to the phenotype category for which they are most significant. Genes associated with multiple phenotypes, including suggestive associations, are denoted with a colored asterisk. Genes with only suggestive associations are underlined. See also Table S2. (B) Manhattan plot for gene-level association analysis for the CD8⁺ T cell phenotype. Each point represents a gene. Positions along the chromosomes are on the x axis, and −log₁₀-transformed p values are on the y axis. The solid red line indicates gene-level significance (p < 2.8 × 10⁻⁶), and the dashed red line indicates suggestive significance (p < 2.9 × 10⁻⁵).

Figure 3.. Altered Subnetworks in Leukocyte Fraction Phenotype

Two statistically significant (p < 0.05) altered subnetworks associated with the leukocyte fraction phenotype in the ReactomeFI 2016 interaction network. Each rectangle represents a gene and is colored according to the gene-level p value. Two genes are connected if their protein products interact in the ReactomeFI 2016 interaction network. Underlined genes are suggestive genes from gene-level analysis. (A) Two suggestive genes, ATR and HSPA2, are part of a larger subnetwork involved in DNA repair. Genes involved in DNA repair or metabolism are indicated by * and §, respectively. (B) A subnetwork containing important members of the nucleotide excision repair and transcription elongation pathway, indicated by # and †, respectively.

Figure 4.. PRS Associations with Immune Infiltration

(A) Workflow for calculating polygenic risk scores (PRSs) of autoimmune disorders based on published GWAS summary statistics, followed by regression of the 17 immune infiltration phenotypes onto PRS. (B) Bar plot showing the strength of association between the phenotypes and PRS for rheumatoid arthritis. The phenotypes are on the x axis, and −log₁₀-transformed p values are on the y axis. Each bar is colored according to the phenotype category. The red line indicates the Bonferroni-corrected significance value (p < 0.0029).