Antigen Presenting Cells from Tumor and Colon of Colorectal Cancer Patients Are Distinct in Activation and Functional Status, but Comparably Responsive to Activated T Cells

SIMPLE SUMMARY: Colorectal cancer (CRC) remains the third most common cancer. Associations between intratumoral T cells, also known as tumor infiltrating lymphocytes (TILs), and the CRC patients’ responses to treatment have been described. Traditionally, TILs and antigen presenting cells (APCs) are studied separately on preserved CRC biopsies, disregarding the adjacent colonic tissue that would also be exposed to the administrated chemotherapy or radiotherapy. Thus, combined data sets on the subset composite and functional capacity of APCs and T cells within the same tumor, as well as colonic tissue, remain infrequent. Our phenotypic and functional comparison of T cell and APC subsets in tumor vs. colon from patients with CRC may give further insights into their propensity to maintain CRC treatment-induced immune responses locally in tumor and off-target colonic tissue. ABSTRACT: Although mouse models of CRC treatments have demonstrated robust immune activation, it remains unclear to what extent CRC patients’ APCs and TILs interact to fuel or quench treatment-induced immune responses. Our ex vivo characterization of tumor and adjacent colon cell suspensions suggest that contrasting environments in these tissues promoted inversed expression of T cell co-stimulatory CD80, and co-inhibitory programmed death (PD)-ligand1 (PD-L1) on intratumoral vs. colonic APCs. While putative tumor-specific CD103+CD39+CD8+ TILs expressed lower CD69 (early activation marker) and higher PD-1 (extended activation/exhaustion marker) than colonic counterparts, the latter had instead higher CD69 and lower PD-1 levels. Functional comparisons showed that intratumoral APCs were inferior to colonic APCs regarding protein uptake and upregulation of CD80 and PD-L1 after protein degradation. Our attempt to model CRC treatment-induced T cell activation in vitro showed less interferon (IFN)-γ production by TILs than colonic T cells. In this model, we also measured APCs’ CD80 and PD-L1 expression in response to activated co-residing T cells. These markers were comparable in the two tissues, despite higher IFN- γ exposure for colonic APCs. Thus, APCs within distinct intratumoral and colonic milieus showed different activation and functional status, but were similarly responsive to signals from induced T cell activation.