Abstract 3709: Deciphering the impact of tumor genetics on immune cell infiltration in major solid cancer types

Abstract

Abstract With the advent of immune therapies including inhibition of the PD-1/PD-L1 axis there is an urgent need to identify cancer patients that benefit from these therapies and to overcome mechanisms of resistance. Here, we analyzed the impact of tumor genetics on the composition of tumor microenvironment across 21 solid cancer types from the TCGA project. Using specific mRNA markers of 10 cell populations (MCPcounter), we estimated the content of T cells, CD8+ T cells, cytotoxic lymphocytes, B lineage cells, NK cells, monocytic lineage cells, myeloid dendritic cells, neutrophils, fibroblasts and endothelial cells in tumor tissues. Immune cell compositions were correlated with mutational load, the activity of 27 mutational signatures (MutSigs) and PD-L1 mRNA expression. Correlation strength was assessed using Spearman’s rho statistics. Multiple testing was addressed using the Benjamini-Hochberg method and FDR control at 5%. MutSig 1 (clock-like, age-related) showed significant positive correlations with immune cell infiltrations in low-grade gliomas, negative correlations in breast cancer, melanoma, stomach cancer, lung and prostate adenocarcinoma, but no significant correlations in the remaining 15 cancer types. Of the two APOBEC-related signatures, MutSig 2 showed positive significant correlations with immune cell infiltrates in cervical cancer, bladder cancer, lung adenocarcinoma, head and neck cancer and thyroid cancer, MutSig 13 in breast and cervical cancer. In particular, correlation of MutSig 2 with cytotoxic lymphocytes was significant in cervical cancer, bladder cancer and lung adenocarcinoma (R = 0.29, R= 0.17 and R = 0.17), the corresponding correlation of MutSig 13 in breast cancer (R = 0.17). MutSig 4 (tobacco smoke-related) showed a positive significant correlation with CD8+ T cells and NK cells in lung adenocarcinoma (R = 0.15 and R = 0.14). In contrast, correlation of MutSig 4 with immune cell infiltrates was non-significant or negative in head and neck cancer. In colorectal cancer, MutSig 6 (defective mismatch repair) showed significant positive correlations with NK cells, cytotoxic lymphocytes, monocytic lineage cells and neutrophils infiltration (R = 0.45, R = 0.37, R = 0.23 and R = 0.19). PD-L1 mRNA expression and immune cell infiltrates correlated positively in all 21 cancer types. In particular, correlation with monocytic lineage cells was positive and significant in all cancer types and strong (R > 0.50) in 12 cancer types. Correlation with T cells was positive and significant in 18 cancer types and strong in 10 cancer types. In summary, pan-cancer analysis of DNA and RNAseq data showed that specific mutational signatures contribute to cancer cell immunogenicity, while the ubiquitous clock-like mutational process did not positively correlate with immune cell infiltrates in 20 of 21 cancer types. Moreover, PD-L1 mRNA expression strongly correlated with infiltrates of immune cells in the majority of cancer types. Citation Format: Jan Budczies, Michael Bockmayr, Frederick Klauschen, Abrecht Stenzinger, Carsten Denkert. Deciphering the impact of tumor genetics on immune cell infiltration in major solid cancer types [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 3709. doi:10.1158/1538-7445.AM2017-3709