Chromosomal instability mediates immune exclusion and response to cytotoxic chemotherapy in colorectal liver metastases

Abstract The genomic drivers of immune exclusion in colorectal cancer liver metastases (CRCLM) remain poorly understood. Chromosomal instability (CIN), resulting in aneuploidy and genomic rearrangements, is the central pathway of mismatch repair-proficient colorectal cancer pathogenesis; however, it is unknown whether CIN impacts the outcomes of patients with limited spread of CRCLM treated with curative intent cytotoxic chemotherapy and surgery. Herein, we examined the relationship between CIN and the molecular subtypes of CRCLM, immune signaling, treatment sensitivity, and patient outcomes in three independent CRCLM patient cohorts. We established that a previously developed 70-gene CIN signature (CIN70) is a reliable measure of CIN, encompassing features of both aneuploidy and cellular proliferation. We demonstrated that tumors with the canonical subtype of CRCLM exhibit elevated levels of CIN and aneuploidy. Genomically unstable tumors were associated with an immune-depleted tumor microenvironment, and patients with genomically unstable tumors were at increased risk for disease progression in adverse metastatic sites, resulting in poor progression-free and overall survival. However, high-CIN tumors were particularly susceptible to DNA-damaging chemotherapies, including topoisomerase inhibitors, as well as radiation therapy. Treatment with genotoxic agents depleted CIN-rich cell populations, which resulted in a concomitant increase in intratumoral CD8+ T-cells in patients with primary rectal, breast, and bladder cancer. Taken together, we propose a mechanistic explanation for why cytotoxic chemotherapy can augment anti-tumor immunity and improve outcomes in patients with genomically unstable cancers.