Abstract The relationship between common germline SNPs that predispose to cancer and the anticancer immune response as measured in tumors is uncharacterized. We investigated this relationship in breast cancer, leveraging availability of four large-scale resources for this cancer type: (1) 159 independent SNP loci associated with overall breast cancer risk at P < 5 x 10-8, including 65 unpublished SNPs, identified by a recent meta-analysis of over 220,000 individuals of European ancestry (EUR) from existing GWAS and new studies from the OncoArray Network (2) Matched germline genotype and tumor transcriptomic profiles from 701 (EUR) breast cancer cases from TCGA (3) a general measure of anticancer immunity - fraction of total immune cells in these TCGA tumors inferred from gene expression signatures by ESTIMATE scoring (Yoshihara et al, Nat Commun 2013) (4) specific measures of anticancer immunity - levels of 15 immune cell types and functions in these TCGA tumors inferred from gene expression signatures by ssGSEA (Rooney et al, Cell 2015). Linear regression with and without adjustment for covariates (age at diagnosis, stage, tumor neoantigen load, tumor ESR1 expression) was used to test association between germline SNP genotype and the tumor anticancer immune response measures. SNPs were evaluated individually and collectively as a polygenic risk score (PRS) weighted by the per-allele log OR derived from the OncoArray analysis. The breast cancer risk-conferring allele for 9 of the 159 SNPs was associated with reduced tumor general immune infiltration (ESTIMATE score) at P < 0.05 both before and after adjustment for covariates. The most significant of these associations with ESTIMATE score (Punadjusted = 0.0003; Padjusted = 0.001) was for rs71801447, the lead SNP at 2q13, a breast cancer risk locus identified by the OncoArray. This SNP was associated at P < 0.05 with 12 of the 15 specific immune cell types and functions both before and after adjustment. The risk allele correlated with reduction in each of these 12 tumor immune phenotypes, with the strongest associations identified for CD4+ regulatory T cell (Padj = 0.003) and CD8+ T cell infiltrates (Padj = 0.007). SNP rs71801447 lies in the 3’-UTR of BCL2L11 and its risk allele was associated with reduced expression of BCL2L11 in the same set of TCGA breast tumors (P = 0.002). Moreover, SNPs in strong LD (r2 > 0.98) with rs71801447 overlapped enhancers in CD4+ and CD8+ T cells and in HMEC and MCF7 breast cells that were predicted to interact with the promoter of BCL2L11 in each of these cell types. Finally, as a PRS, breast cancer risk was significantly associated with reduced tumor type I interferon activity (Punadj = 0.006; Padj = 0.02). Our findings implicate BCL2L11, a well-known regulator of T and breast cancer cell apoptosis, as a potential link between germline risk SNPs and immune response to tumors in breast cancer and suggest that modulating antitumor immunity may be a mechanism of action for some established risk loci. Note: This abstract was not presented at the meeting. Citation Format: Siddhartha Kar, Jonathan Tyrer, Paul Pharoah, Breast Cancer Association Consortium (BCAC). Common germline risk loci and the tumor anticancer immune response in breast cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 1299. doi:10.1158/1538-7445.AM2017-1299