Abstract
The presence of activated T cells in colorectal cancer tissues is a strong predictor of patient survival. Our previous studies have shown that regulatory T cells (Treg) are able to reduce T cell transendothelial migration in vitro and accumulation of effector T cells in intestinal tumors in vivo in the murine APCMin/+ model for microsatellite stable intestinal tumors. In this study, we investigated the effect of Treg depletion on the density and effector functions of different TCRαβ+ and TCRγδ+ T cell populations in intestinal tumors. We used the APCMin/+\\DEREG mouse model, which harbor a diphtheria toxin receptor under the control of the FOXP3 promoter, to deplete Treg in tumor bearing mice. We found that the density of conventional TCRαβ+CD8αβ+ T cells was significantly increased in Treg-depleted tumors in comparison with Treg-proficient tumors. Furthermore, TCRαβ+CD8αβ+ T cells showed increased proliferation and activation as well as increased Granzyme B and IFN-γ production in Treg-depleted tumors. In sharp contrast, the densities and effector functions of TCRαβ+CD8αα+ T cells and TCRγδ+ T cells remained unchanged by Treg depletion. We also documented a distinct population of IL-17A+TNF+ TCRγδ+CD8− T cells in tumors, which were not affected by Treg depletion. We conclude that Treg depletion affects only conventional TCRαβ+CD8αβ+ T cells in intestinal tumors, while unconventional T cells and T cells in unaffected tissue are not altered. Immunotherapies aimed at depleting Treg from tumors may thus be a viable option for reinvigoration of conventional cytotoxic T cells with a Th1 cytokine profile.
Highlights
Colorectal cancer (CRC) is one of the most common cancer diseases worldwide [1]
We used the A PCMin/+ mouse model of spontaneous intestinal tumors to investigate the functions of different cytotoxic T cell populations in tumors compared to unaffected mucosa and the effect of Treg depletion on these populations
We could show that Treg depletion resulted in improved T cell activation, proliferation, and cytokine and Granzyme B (GrzB) production, but only of conventional TCRαβ+CD8αβ+ T cells and selectively in the tumor tissue
Summary
Colorectal cancer (CRC) is one of the most common cancer diseases worldwide [1]. There has been an improvement in the survival of CRC patients over the last decades [2]; while some patients respond well to therapies, others do not. Microsatellite instability (MSI), resulting from mutations leading to inactivation of the mismatch repair genes, is used as a diagnostic marker in the clinic. The 10–15% of patients that are MSI-High (MSI-H) usually show a better disease-free and overall survival [3] than the remaining 85–90% of microsatellite stable (MSS) CRCs. MSS tumors typically show chromosomal instabilities and mutations in the adenomatous polyposis coli (APC) gene giving rise to both familial adenomatous polyposis and most of the sporadic cancers [4]. MSS tumors are usually characterized by poor infiltration of Th1type lymphocytes, which are classically defined as CD4+
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