Variation in tumor-associated immune profiles and colorectal cancer outcomes

Considerable variability in tumor-associated immune responses exists across racial/ethnic populations. These variations may explain part of the observed disparities 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 diversity of TIL responses observed among CRCs remain largely unknown, and the influence of race/ethnicity and genetic ancestry have been underexplored. In a recent study comparing CRCs from African Americans and non-Hispanic Whites, differences in lymphocytic reactions were observed to partially explain the survival disparity between the two groups. No data is available for other racial/ethnic groups. Prior research has also been limited by relying solely on self-reported race/ethnicity, a significant limitation. Studies show that self-report does not fully or accurately reflect the genetic diversity present in admixed minority populations. 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 racial/ethnic groups. Studies in the genertically admixed Latinx population offer notable advantages including a unique opportunity to simultaneously tease out the contributions of multiple ancestral backgrounds (e.g. African, European, Indigenous American) to variability in immune function. 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 disparities (i.e. observed across populations defined by ethnicity and by genetic ancestry) using existing resources from the Hispanic Colorectal Cancer Study, the Puerto Rico Biobank, the Total Cancer Care Protocol, and the Molecular Epidemiology of Colorectal Cancer Study . We will address three aims: (1) quantify CRC-associated T cell profiles in Latinxs from diverse genetic ancestral backgrounds using DNA- and protein-based approaches; (2) investigate the independent associations of genetic ancestry, epidemiologic factors, and clinical variables with T cell profiles in the tumor microenvironment of Latinx CRCs; and (3) compare CRC-associated T cell profiles between Latinx and NHW populations. This study is unique in leveraging the ancestral diversity of Latinos to understand the relationships between race/ethnicity, germline genetics, tumor immunobiology, and cancer disparities. Results will provide new avenues for understanding immunological factors contributing to disproportionate treatment response and mortality in diverse populations of patients with CRC.