BackgroundThere is indirect evidence that T cell responses can control the metastatic spread of colorectal cancer (CRC). However, an enrichment of CD4+Foxp3+ regulatory T cells (Tregs) has also been documented.ObjectiveTo evaluate whether CRC promotes Treg activity and how this influences anti-tumour immune responses and disease progression.MethodsA longitudinal study of Treg activity on a cohort of patients was performed before and after tumour resection. Specific CD4+ T cell responses were also measured to the tumour associated antigens carcinoembryonic antigen (CEA) and 5T4.ResultsTregs from 62 preoperative CRC patients expressed a highly significant increase in levels of Foxp3 compared to healthy age-matched controls (p=0.007), which returned to normal after surgery (p=0.0075). CD4+ T cell responses to one or both of the tumour associated antigens, CEA and 5T4, were observed in approximately two-thirds of patients and one third of these responses were suppressed by Tregs. Strikingly, in all patients with tumour recurrence at 12 months, significant preoperative suppression was observed of tumour-specific (p=0.003) but not control CD4+ T cell responses.ConclusionThese findings demonstrate that the presence of CRC drives the activity of Tregs and accompanying suppression of CD4+ T cell responses to tumour-associated antigens. Suppression is associated with recurrence of tumour at 12 months, implying that Tregs contribute to disease progression. These findings offer a rationale for the manipulation of Tregs for therapeutic intervention.
Prolonged patient survival after surgical resection, is associated with a higher cytotoxic and memory T cell density within colorectal cancers (CRC). High endothelial venules (HEVs) are specialized blood vessels present in secondary lymphoid organs (SLO) that allow ingress of naïve and central memory T cells from the blood. It has been proposed that HEVs in tumors might serve as a similar route of entry for lymphocytes into the tumor and result in an improved prognosis. The present study aimed to characterize HEVs and their microenvironment in resected tumors from colorectal cancer patients (n = 62). We observed HEVs in association with lymphoid aggregates in 49 out of 62 patients. However, these HEV+ lymphoid aggregates were largely at the invasive margin of the tumor and although there was an association with lymphocytes and HEVs at the invasive margin (p = 0.002) there was only a very weak association with tumor infiltrating lymphocytes. Indeed, lymphoid aggregates were associated with more advanced disease (Dukes’ stage C) and did not indicate a favorable prognosis.
Human CD4+ αβ T cells are activated via T-cell receptor recognition of peptide epitopes presented by major histocompatibility complex (MHC) class II (MHC-II). The open ends of the MHC-II binding groove allow peptide epitopes to extend beyond a central nonamer core region at both the amino- and carboxy-terminus. We have previously found that these non-bound C-terminal residues can alter T cell activation in an MHC allele-transcending fashion, although the mechanism for this effect remained unclear. Here we show that modification of the C-terminal peptide-flanking region of an influenza hemagglutinin (HA305−320) epitope can alter T-cell receptor binding affinity, T-cell activation and repertoire selection of influenza-specific CD4+ T cells expanded from peripheral blood. These data provide the first demonstration that changes in the C-terminus of the peptide-flanking region can substantially alter T-cell receptor binding affinity, and indicate a mechanism through which peptide flanking residues could influence repertoire selection.
scite is a Brooklyn-based organization that helps researchers better discover and understand research articles through Smart Citations–citations that display the context of the citation and describe whether the article provides supporting or contrasting evidence. scite is used by students and researchers from around the world and is funded in part by the National Science Foundation and the National Institute on Drug Abuse of the National Institutes of Health.
hi@scite.ai
10624 S. Eastern Ave., Ste. A-614
Henderson, NV 89052, USA
Copyright © 2024 scite LLC. All rights reserved.
Made with 💙 for researchers
Part of the Research Solutions Family.