PROJECT SUMMARY This application is being submitted in response to the Notice of Special Interest (NOSI) identified as "NOT-CA- 24-032.” Racial and ethnic minority populations in the U.S., including the Hispanic/Latino/a/x/e (henceforth referred to as Latino) community, are substantially underrepresented in cancer research. This creates missed opportunities for investigating disparities and evaluating strategies to improve health equity. Importantly, the vast heterogeneity in the Latino population with respect to genetic ancestry, sociodemographics, health behaviors, and risk factors is often overlooked, leading to unaddressed health disparities across diverse Latino communities (e.g. Mexican, Central/South American, Puerto Rican, Cuban). For example, in colorectal cancer (CRC), evidence suggests that Puerto Rican and Cuban Latinos individuals may experience worse CRC mortality than Mexican Latino and non-Hispanic white individuals, even after controlling for sociodemographic factors, stage and access to care. To facilitate investigation of biological contributors to CRC disparities within the Latino population, our team established the Latino Colorectal Cancer Consortium (LC3) in 2019. The parent award for this proposal (R01CA248931) leverages LC3 data and biospecimens to uncover how ethnicity, genetic ancestry, epidemiologic factors, and clinical variables independently influence immune responses to CRC. This is timely and critical research as immunotherapy has been a paradigm-shifting strategy for saving lives, but it has not worked in all people. We and others have shown the importance of tumor-associated T cell responses as positive prognostic and predictive indicators, as well as substantial differences in immune “hot” tumors across racial and ethnic populations. LC3 is a unique resource, but Puerto Rican and Cuban communities, the groups experiencing the highest CRC mortality burden, need greater representation. To begin filling this gap, we launched a pilot study using institutional funds at Cleveland Clinic. The Cleveland Clinic Latino Epidemiology (CCLE) Cohort, which will become a sub-cohort of LC3, began accruing patients with CRC in northeast Ohio (Cleveland) and southeast Florida (Weston), with all regulatory and operational details implemented as of February 2024 (i.e. IRB approval, Spanish-speaking research coordinators, patient questionnaire, biospecimen collection). This supplement will build upon institutional commitment for recruiting, collecting survey data, and obtaining germline samples for 100 CCLE participants by permitting tumor somatic and immune landscape characterization on a subset for comparisons across Latino groups, which cannot otherwise be supported. In Aim 1, we will integrate demographic (e.g. age, sex, country of origin), social elements of health (e.g. area deprivation, BMI, physical activity), and clinical (e.g. survival) data from CCLE participants into the LC3 pipeline. In Aim 2, we will obtain and pathol...