Defining the role of tumoral MHC Class I Expression in Mediating Colorectal Cancer Racial Disparities

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PROJECT SUMMARY Compared to Whites, African American/Blacks (AA/B) have a substantially higher (40-50%) colorectal cancer (CRC) mortality rate that is a function of both higher incidence and lower survival rates. Our long-term goal is to understand the differences in immune response that influence this disparity in CRC mortality. Emerging studies suggest alterations in T cell presence and function in AA/B contribute to CRC disparities, and AA/B CRC patients with low immune infiltrate have particularly poor outcomes. We have found that AA/B CRC patients have disproportionally reduced tumoral MHC class I expression compared with White patients. As MHC class I is critical for presentation of tumor antigens to CD8+ T cells, these results suggest a critical immune mediated mechanism that drives the differences in survival times between AA/B and White patients. The objectives of this project are to understand the mechanisms relevant to T cell alterations within the tumors of AA/B versus White patients and to develop improved biomarkers and therapies to reduce CRC racial disparities. Our central hypothesis is that reduced tumoral MHC class I expression drives T cell alterations to enhance tumoral immune escape in CRC from AA/B patients compared with White patients. To test this hypothesis, we have developed robust multispectral imaging capability for studying the relationship between MHC class I expression and CD8+ T cell frequency, localization, phenotype, and function. In parallel, we have developed an autologous humanized CRC TIL-PDX mouse model, created with matched patient-derived tumor and tumor infiltrating T cells (TILs) to investigate CRC disparities. This completely unique approach will be undertaken by a multi-disciplinary team, which includes a surgeon-scientist with expertise in CRC oncology, a cancer immunologist, and a cancer disparities basic researcher. In Aim 1, we will define CD8+ T cell biology in the context of tumoral MHC class I loss in AA/B versus White CRC patients. We will perform both multispectral imaging of archival tumor samples and phenotypical/ functional studies of fresh samples to define essential differences between AA/B and White tumors. In Aim 2, we will evaluate whether TIL-PDX mice generated from AA/B versus White CRC tumors exhibit differential T cell biology and anti-tumor immunity in the context of tumoral MHC class I expression. We expect that the use of the CRC TIL-PDX mouse model will recapitulates a patients’ tumor immunity in a manner not previously possible to determine the differences in immune mediated processes. In Aim 3, we will assess the ability of IL-15 as a therapy to overcome AA/B tumoral MHC class I loss using a syngeneic CRC tumor-bearing mice. The positive impact of this work will be an improved understanding of the differences in immune-mediated mechanisms to understand disparities associated with CRC patient outcomes and to develop a therapeutic approach to help AA/B CRC patients.