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

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.

A Fraction of CD8+ T Cells from Colorectal Liver Metastases Preferentially Repopulate Autologous Patient-Derived Xenograft Tumors as Tissue-Resident Memory T Cells

“…Whereas CD103+CD8+ T RM cells were readily detected in both CRLM and the adjacent liver, T RM cells that co-expressed CD39 were mainly present in CRLM. In line with our previous report on T RM cells in primary CRC [ 13 ], the CD103+CD8+ T RM cells in CRLM and the liver also had high expression of co-inhibitory markers, which indicate continuous T cell activation. In this regard, previous reports have identified CD39 as a marker of extended T cell activation [ 29 ] or tumor-specific TILs in CRC [ 12 ], which encouraged us to functionally compare CD103+CD8+ T RM cells from CRLM vs. liver.…”

“…The consensus within the field of tumor immunology underpins the important role of TILs in CRC with regard to prognosis, post-treatment clinical outcome and treatment strategies [ 3 , 4 , 5 , 6 , 7 ]. Although functionally distinct TIL subsets exist in CRC [ 13 , 24 , 25 , 26 ], reports on TILs within CRLM are relatively scarce. Thus, we characterized T cell subsets in CRLM and the adjacent liver tissue.…”

“…Cell suspensions were stained as previously described [ 13 , 24 , 27 ]. Briefly, cell viability was determined by Zombie Red Fixable viability dye (Biolegend, San Diego, CA, USA).…”

“…As a high level of CD8+ TILs is favorable in CRC, identification of tumor-specific TILs has been pursued to potentially refine the prognosis. In this regard, putative CD103+CD39+CD8+ tumor-reactive TILs in primary tumors have previously been assessed by us and others [ 11 , 12 , 13 ]. These CD8+ TILs express CD103 (integrin alpha E), which is involved in tissue retention, and upregulate CD39 (ectonucleotidase) due to, e.g., continuous activation, which suggests that they exert their effector functions while steadily residing in the tumor as T RM cells.…”

Cancer Immunology and Immunotherapies: Mechanisms That Affect Antitumor Immune Response and Treatment Resistance

“…This finding uncovers a novel mechanism that regulates dendritic cells’ migration from the tumor tissue, a critical factor in antigen presentation and in antitumor immune responses. Liang et al [ 12 ] further contribute to the body of research regarding antigen-presenting cells. The authors performed an in-depth analysis of antigen-presenting cells in the human colorectal cancer microenvironment.…”