Mechanistic insights into the interactions between cancer drivers and the tumour immune microenvironment

Abstract

The crosstalk between cancer and the tumour immune microenvironment (TIME) has attracted significant interest because of its impact on cancer evolution and response to treatment. Despite this, cancer-specific tumour-TIME interactions and their mechanisms of action are still poorly understood. Here we identified the interactions between cancer-specific genetic drivers and anti- or pro-tumour TIME features in individual samples of 32 cancer types. The resulting 477 TIME drivers are multifunctional genes whose alterations are selected early in cancer evolution and recur across and within cancer types. Moreover, the anti-tumour TIME driver burden is predictive of overall response to immunotherapy. Focusing on head and neck squamous cancer (HNSC), we rebuilt the functional networks linking specific TIME driver alterations to the TIME state. We showed that TIME driver alterations predict the immune profiles of HNSC molecular subtypes, and that deregulation of keratinization, apoptosis and interferon signalling underpin specific driver-TIME interactions. Overall, our study provides a comprehensive resource of TIME drivers giving mechanistic insights into their immune-regulatory role.