Abstract D121: Predicting African American and European American patient response to kidney cancer immunotherapy by stage using the tumor microenvironment
Authors: Cobb Jacquelyn , Williams Heinric , Mitchell Khadijah A. 
Published: September 2020

Background Kidney cancer ranks as a top ten leading site of new cancer cases (~64,000) in the US each year. Renal Cell Carcinoma (RCC) is the predominant type of kidney cancer (~90% cases). The most common RCC subtypes include clear cell RCC (ccRCC, 75%), papillary RCC types I and II (pRCC I and II, 5% and 10%), and chromophobe RCC (chRCC, 5%). RCC subtypes have distinct responses to immunotherapy. Combination checkpoint inhibitors are the first-line treatment for advanced stage ccRCC. Unfortunately, response varies in advanced stage patients, suggesting stage-specific differences in tumor biology. Tumor infiltrating lymphocytes (TILs) in the tumor microenvironment (TME) have been shown to directly influence checkpoint inhibitor response. African Americans (AAs) have higher RCC incidence rates than European Americans (EAs) for reasons that are unclear. Biological determinants of this cancer health disparity have been largely understudied. To our knowledge, no study to date has profiled the TME by stage in AA and EA RCC patients and explored its usefulness as a predictor of checkpoint inhibitor response. Hypothesis TIL abundances and composition varies by stage between AAs and EAs with RCC. Methods Downloaded mRNA-sequencing and clinical data for 531 ccRCC patients, 52 Type I pRCC patients, 66 Type II pRCC patients, and 66 chRCC patients in the TCGA discovery cohort. Differential expression analyses for checkpoint inhibitor drug targets (PD-1, PD-L1, and CTLA-4) were carried out. CIBERSORT, a computation tool that quantifies abundances for 22 TILs based on gene expression, was used to characterize the TME. 1-way ANOVAs between Stages I-IV were performed with GraphPad Prism 8. Significant racial differences for relevant TILs were determined using two-tailed unpaired Welch t tests. Kidney cancer immunotherapy drug responses were inferred based on published clinical studies. Results PD-1 and CTLA-4 significantly increased in advanced stage ccRCC patients. 6/22 TILs showed stage-specific increases and decreases in ccRCC patients. Interestingly, three of these (follicular helper T cells, regulatory T cells, and CD8+ T cells) showed the same trend as the checkpoint inhibitor targets. In pRCC I and II, some TILs also demonstrated a linear increase by stage (Both: regulatory T cells, M1 macrophages; Type II only: naive B cells). M2 macrophage abundance increased significantly by stage in chRCC patients. When comparing AA (n=55) and EA (n=461) ccRCC patients, follicular helper T cells and regulatory T cells increased by stage in EA only. CD8+ T cells increased in abundance in both racial groups. Regulatory T cells and M2 macrophages have been reported to mediate clinical response to checkpoint inhibitor immunotherapy. Conclusions/Future Directions Our data suggests AA and EA RCC patients with advanced stage disease will respond differently to kidney cancer immunotherapy due to TME differences, namely TIL abundance and composition. Future studies include validating these findings in the expO cohort.

Citation Format: Jacquelyn Cobb, Heinric Williams, Khadijah A. Mitchell. Predicting African American and European American patient response to kidney cancer immunotherapy by stage using the tumor microenvironment [abstract]. In: Proceedings of the Twelfth AACR Conference on the Science of Cancer Health Disparities in Racial/Ethnic Minorities and the Medically Underserved; 2019 Sep 20-23; San Francisco, CA. Philadelphia (PA): AACR; Cancer Epidemiol Biomarkers Prev 2020;29(6 Suppl_2):Abstract nr D121.