Dissecting the role of copy number alterations in cancer immune evasion

The immune system is a major barrier to tumor progression, and cancer cells must evolve multiple strategies to evade immune surveillance. The clinical success of immunotherapy in subsets of patients underscores the critical role of anti-tumor immunity in cancer control. However, genetic analyses of cancer drivers have not identified bona fide immune-modulatory genes frequently altered by point mutations. In contrast, cancer genomes commonly harbor recurrent copy number alterations (CNAs), which change the dosage of specific genomic regions, can affect up to 30% of the cancer genome, and are associated with immune evasion. Despite their prevalence, the functional impact of specific CNAs on immune surveillance remains poorly understood, in part because current models do not accurately recapitulate the complexity of these chromosomal alterations. To address this, we have developed novel genome engineering approaches and applied them in syngeneic mouse models of pancreatic and ovarian cancer. Using this framework, we are beginning to dissect how recurrent chromosomal deletions and amplifications shape anti-tumor immunity, and how these alterations may reveal new therapeutic vulnerabilities