oa Defining genetic modulators of intratumoral immune response in breast cancer through a system biology approach

Breast cancer is the most common type of tumor in women in the MENA region and it represents about 20% of the cancers diagnosed every year in Qatar. Although the implementation of cancer therapy has led to an improvement of patients' survival, metastatic breast cancer remains an incurable condition. Immunotherapy is emerging as an innovative therapeutic tool able to cure in some cases established metastatic tumors such as melanoma. There is a growing interest in exploring this fascinating approach in breast cancer. However, little is known about the immune biology of this aggressive disease. Studies from our and other groups have described intratumoral immune gene signatures associated with better responsiveness to immunotherapy and prolonged survival (Galon, Angell, Bedognetti and Marincola, Immunity 2013; PMID: 23890060). In general, these gene signatures imply the activation of interferon stimulated genes (e.g. IRF1 and STAT1), the recruitment of lymphocytes through CXCR3/CCR5 ligand chemokines, and the activation of immune-effector functions such as PRF1 and GZM1 (Wang, Bedognetti, Marincola, JCO 2013; PMID: 23715576). We refer to these genes as the Immunologic-Constant-of-Rejection (ICR) (Bedognetti, Wang, Sertoli, Marincola, Exp Rev Vacc, 2010; PMID: 20518712). The activation of the ICR pathways is accompanied by the counter-activation of immune-regulatory mechanisms such as the expression of PD-L1 and IDO1. Based on these observations, we hypothesize that tumors can be divided in two opposite phenotypes (Bedognetti, Hendrickx, Marincola, Miller, Curr Opin Onc 2015; PMID: 26418235). The first phenotype displays the activation of pro-inflammatory (ICR) and immune-regulatory mechanisms and is characterized by a favorable prognosis and responsiveness to immune manipulations. The second phenotype lacks these two characteristics and is associated by a poor prognosis and resistance to immune manipulations. Whether the development of such different immune phenotypes is influenced by the intrinsic genetics of the tumor cells is presently unclear. The understanding of genetic mechanisms associated with differential immune response can lead the development of targeted approaches. To answer this critical question we analyzed copy number variation, exome and RNA sequencing data from the The Cancer Genome Atlas (TCGA) breast cancer dataset. By using consensus clustering analysis based on RNA-seq data of more than 1000 breast cancer samples, we defined four immunophenotypes characterized by progressive expression of the ICR genes (ICR1