Variation in tumor-associated immune profiles and colorectal cancer outcomes

Considerable variability in tumor-associated immune responses exists across populations. These variations may explain part of the observed differences in response to cancer therapies, particularly immunotherapy, and treatment outcomes. In colorectal cancer (CRC), the intensity and composition of tumor infiltrating lymphocytes (TIL) are established prognostic and predictive indicators. However, factors contributing to the variability in TIL responses observed among CRCs remain largely unknown. In a recent study, differences in lymphocytic reactions to CRC were observed to partially explain the survival difference between groups of people from different backgrounds. Limited data is available for other groups that broadly represent the US population. Prior research has also been limited by relying solely on self-reported information, a significant limitation. Studies show that self-report does not fully or accurately reflect genetic background. We hypothesize that ancestral genetic architecture is important for shaping immune-related determinants of CRC outcomes given the differential efficiency of immune function observed across populations. Here, we will test the hypothesis that genetic ancestry is independently associated with differences in tumor-associated T cell profiles that contribute to CRC outcome differences across populations using existing resources. We will address three aims: (1) quantify CRC-associated T cell profiles using DNA- and protein-based approaches; (2) investigate the independent associations of patient factors, epidemiologic variables, and clinical characteristics with T cell profiles in the tumor microenvironment; and (3) compare CRC-associated T cell profiles between different population groups. This study will understand the relationships between germline genetics, tumor immunobiology, and cancer differences. Results will provide new avenues for understanding immunological factors contributing to differences in treatment response and mortality across patients with CRC.