Abstract B13: Integrative genomic and transcriptomic analysis of 775 human cancer cell lines reveals tumor-derived immune programs and their regulators

Abstract

Abstract The role of tumor cell-derived immune factors in the development of cancer and tumor immunity remains poorly understood. We hypothesized that tumors express recurrent and stable immunoregulatory programs that impact cancer growth and immunity. To identify these programs, we performed an unbiased integrative analysis of chromosomal copy number aberrations and gene expression analysis on 775 primary solid tumor cell lines, derived from 23 different tissues of origin. Using modified versions of GISTIC 2.0 and CONEXIC, a Bayesian module network method, we identified cancer drivers that correlated with specific transcriptional regulatory programs across multiple cell lines (after considering confounding variables, including histology, sub-histology, ethnicity, gender, center of collection, experimental batches and unknown variables using Surrogate Variable Analysis). We identified a total of 60 amplified and 222 deleted somatic regions, of which 52% contained a candidate driver gene whose expression was associated with the expression of a target module. The driver genes consisted of putative novel and known cancer drivers, including deletions in CDKN2A-CDKN2B (q< 4.2E-176), WWOX (q< 5.3E-100), and amplifications in MYC (q< 2.1E-81) and CCND1 (q< 1.4E-44) genes. The target modules were enriched for known cancer-dysregulated processes, including cell cycle (q< 2.1E-91) and DNA damage/repair (q< 9.3E-50), validating the analysis. We identified and focused on immune programs common to several tissues of origin, including a type I interferon-related program (q<9.8E-26), which is likely to impact the tumor immune microenvironment. To validate our predictions, we functionally investigated 8 cell lines with high versus 8 with low expression of the interferon-related immune regulatory program. We validated activation of the pathway at the protein level and found that it was sustained by secreted factors. We found drivers of this program using CRISPR/Cas9 single guide RNAs and small molecule inhibitors, and showed that cancer cells expressing this program modulated activation of co-cultured immune cells. The finding of a stable tumor-derived immune program should help point to new targets for cancer therapy. Note: This abstract was not presented at the conference. Citation Format: Alexandra-Chloe Villani, Ye Chun, Raktima Raychowdhury, Weibo Li, Thomas Eisenhaure, Aviv Regev, Nir Hacohen. Integrative genomic and transcriptomic analysis of 775 human cancer cell lines reveals tumor-derived immune programs and their regulators. [abstract]. In: Proceedings of the AACR Special Conference on Tumor Immunology and Immunotherapy; 2016 Oct 20-23; Boston, MA. Philadelphia (PA): AACR; Cancer Immunol Res 2017;5(3 Suppl):Abstract nr B13.