Project 2: Chemotherapy-induced Immunomodulation in Colon Cancer

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PROJECT SUMMARY: PROJECT-2 (This Project is identical for all three Partnering Institutions) The Morehouse School of Medicine (MSM), Tuskegee University (TU), and the University of Alabama at Birmingham O’Neal Comprehensive Cancer Center (UAB OCCC) U54 partnership fosters collaborative research, educational and outreach activities among the institutions and the communities they serve. This joint research project between TU and UAB OCCC aligns with those objectives. Fewer than 15% of colorectal cancer (CRC) patients may benefit from current immunotherapies. The mechanisms for these refractory states are not completely understood, and an immense gap remains in our knowledge of the immune factors that are involved in CRCs, especially those undergoing therapy. We propose to develop combination therapy strategies that modulate the immune microenvironment in CRCs. We aim to accomplish this by elucidating chemotherapy- inducible immunomodulation in CRCs and identifying alternative targets adaptable to personalized medicine. In preliminary in vitro studies, we found a predominantly inflammatory and T-cell modulating cytokine profile after treatment with camptothecin, including upregulation of SPP1, CXCL8, SOCS1, IL12, CXCL1 and CD274/PDL1. Further, CD44, the cognate receptor for SPP1, was one of the up-regulated genes in stage 3 recurrent CRC. SPP1 is a prognostic biomarker, with low expression being associated with better survival, and has emerged as a signature microenvironment marker of poor prognosis. Therefore, we hypothesize that topoisomerase inhibition therapy induces both immunomodulatory mechanisms and instructive biomarkers that can guide combination therapy tailored to individual patients. We will use in vitro, ex vivo, preclinical, organoid, and PDX models to pursue these Specific Aims: 1) Identify immune modulatory cytokines in patient-derived primary colon cancer cells treated with irinotecan, a clinical chemotherapy agent; 2) Establish metronomic irinotecan as an inducer of immunoregulatory and theranostic biomarkers; and 3) Identify the role of SPP1-CD44 and CXCL1-CXCR2 signaling pathways in topoisomerase inhibition therapy. Despite the success of standard care drugs in the treatment of CRC, durable and relapse-free outcomes are still not achievable. Currently, immunotherapy using checkpoint inhibitors is also unavailable for most CRC patients. By identifying the therapy-induced immune landscape and the functions of induced cytokines in both Caucasian and African American origins, results from this study will elucidate the mechanisms regulating immune response after chemotherapy, and help us to develop a strategy to combine conventional therapy with immunotherapy for CRC patients.