Abstract 844: DNA methylation-derived immune cell profiles and risk of cancers in Black participants in the ARIC Study

Abstract Background: Prior cohort studies assessing cancer risk based on immune cell subtype profiles have predominantly focused on White populations. This limitation can obscure vital insights into how cancer risks vary across races, ethnicities, or exposures. This study was designed with the purpose of examining associations between pre-diagnostic immune cell profiles and cancer risk in Black participants. Methods: In this study, DNA methylation was measured in blood samples collected between 1993 and 1995 from a subset of 2,467 Black participants in the Atherosclerosis Risk in Communities (ARIC) prospective cohort study. Immune cell subtype proportions were estimated using deconvolution based on leukocyte DNA methylation markers. The analysis included 668 incident cancers ascertained between time of blood draw and 2015. Cox proportional hazards regression models were used to analyze the association between immune cell subtype proportions and cancer incidence (all cancers; lung, breast, and prostate cancers). Models controlled for age, sex, BMI, self-reported smoking status, self-reported and methylation-derived smoking pack-years, postmenopausal hormone use, and batch effect, along with other cancer-specific factors. Results: Increased T regulatory cell (Treg) proportions were associated with significantly higher risk of lung cancer (HR: 1.22, 95% CI = 1.06, 1.41 per percent increase; n = 84 cases) and suggestively higher risk of all cancers. Increased B memory cell proportions were associated with significantly higher risk of prostate cancer (HR: 1.17, 95% CI = 1.04, 1.33; n = 173 cases), all cancers (HR: 1.13, 95% CI = 1.05, 1.22), and suggestively higher risk of lung cancer. Increased CD8+ naïve cell proportions were associated with suggestively lower risk of lung cancer and all cancers, and significantly lower risk of all cancers in participants over the median age of 55 years (HR: 0.91, 95% CI = 0.83, 0.98). Cancer risks for other immune cell subtypes were null. Conclusions: These results in Black participants align closely with prior findings in largely White populations. Deconvolution allowed for the extension of work on cancer immunity (which has largely focused on major immune cell types) to immune cell subtypes like B memory cells and CD8+ naïve cells. The results are consistent with Tregs initiating and accelerating cancer development by impeding the usual protective immune response. A large reservoir of CD8+ naïve cells may allow for a more targeted and efficient elimination of malignant clones. Further studies should assess these relationships in other cancer types and better elucidate the interplay of B cells in theorized mechanistic processes. This study provides insight into the role of immune cell subtypes in cancer risk among Black men and women. Funding: NHLBI, NCR, NPCR Citation Format: Christopher S. Semancik, Naisi Zhao, Devin Koestler, Eric Boerwinkle, Jan Bressler, Karl Kelsey, Elizabeth A. Platz, Dominique S. Michaud. DNA methylation-derived immune cell profiles and risk of cancers in Black participants in the ARIC Study [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 844.