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Colon cancer and the immune system: the role of tumor invading T cells.

ABSTRACT: Colon cancer is still one of the leading causes of cancer death worldwide. Although the host immune system has been shown to react against tumor cells, mainly through tumor infiltrating lymphocytes and NK cells, tumor cells may utilize different ways to escape anti-tumor immune response. Tumor infiltration of CD8+ and CD4+ (T-bet+) effector T cells has been attributed to a beneficial outcome, and the enhancement of T cell activation through T cell receptor stimulation and co-stimulatory signals provides promising strategies for immunotherapy of colon cancer. Growing evidence supports a role for the Fas/FasL system in tumor immunology, although the mechanisms and consequences of FasL activation in colon cancer are not completely understood. In animal models, depletion of regulatory T cells (CD4+ CD25+ T cells) can enhance the anti-tumor immune response under certain conditions. Taken together, recent insights in the immune reaction against colon carcinoma have provided new approaches to immunotherapy, although much remains to be learned about the exact mechanisms.

SUBMITTER: Waldner M

PROVIDER: S-EPMC4087478 | biostudies-literature | 2006 Dec

REPOSITORIES: biostudies-literature

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Colon cancer and the immune system: the role of tumor invading T cells.

Waldner Maximilian M Schimanski Carl-C CC Neurath Markus-F MF

World journal of gastroenterology 20061201 45

Colon cancer is still one of the leading causes of cancer death worldwide. Although the host immune system has been shown to react against tumor cells, mainly through tumor infiltrating lymphocytes and NK cells, tumor cells may utilize different ways to escape anti-tumor immune response. Tumor infiltration of CD8+ and CD4+ (T-bet+) effector T cells has been attributed to a beneficial outcome, and the enhancement of T cell activation through T cell receptor stimulation and co-stimulatory signals ...[more]

PMID: 17143936

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Project description:BackgroundCluster of differentiation 47 (CD47), a transmembrane protein, plays a critical role in regulating cellular functions and maintaining immune homeostasis. Its expression has been shown to influence cancer prognosis. In this study, we investigated the role of CD47 in tumor progression in colon adenocarcinoma (COAD) and evaluated its potential as a target for immunotherapy.Materials and methodsWe analyzed surgical samples from 96 COAD patients. Immunohistochemical analysis was performed on 90 samples, while the remaining 6 were subjected to multiplex immunofluorescence. To explore the association between CD47 expression and clinicopathological characteristics, we integrated transcriptome data from The Cancer Genome Atlas and the Gene Expression Omnibus using R software. The Tumor Immune Estimation Resource and Kaplan-Meier plotter were utilized to assess the relationship between CD47 expression, patient prognosis, and immune infiltration. Furthermore, the single-cell Tumor Immune System Interaction Database was used to examine the correlation between CD47 expression and the tumor microenvironment (TME). All included patients gave oral and written informed consent. The study was approved by the Ethics Committee of 3201 Hospital (full name: Medical Ethics Committee of 3201 Hospital).ResultsCD47 was found to be overexpressed in various tumors, including COAD. Higher CD47 expression was significantly associated with more advanced tumor stages, including TNM staging, T staging, and N staging (P < 0.05). A robust correlation was observed between CD47 expression and immune cell infiltration in COAD. Patients with elevated CD47 expression tended to have longer disease-free intervals, although this benefit was diminished in cases with high infiltration of M1 macrophages. The immunosuppressive function of CD47 primarily acted through the CD47/SIRPα pathway. Additionally, distinct cellular compositions and distributions were identified between primary and metastatic COAD, underscoring the heterogeneity of the TME. CD47 also influenced the TME by modulating cytokine and cytokine receptor interactions.ConclusionCD47 represents a promising prognostic biomarker and a potential target for immunotherapy in COAD. These findings provide new insights into therapeutic strategies aimed at modulating the TME and improving patient outcomes.

Project description:IntroductionThe chemoattractant receptor, G protein-coupled receptor 15 (GPR15), promotes colon homing of T cells in health and colitis. GPR15 function in colon cancer is largely unexplored, motivating our current studies.MethodsIn human study, immune cells were isolated from tumor tissues and healthy surgical tumor margins (STM), and their proportions as well as expression of GPR15 was analyzed by flow cytometry. In mouse studies, colon cancer was induced in GPR15-deficient (KO) and GPR15-suficient (Het) mice using azoxymethane (AOM) and dextran sulfate sodium (DSS) solution in drinking water. Serial endoscopy was performed in mice to monitor and visualize the distal region of colon. Mice were euthanized 10 weeks after the initial DSS administration, and the colon length and the number of polyps were recorded. Next, we identified the effects of GPR15L on established tumors in the MC38-colorectal cancer (CRC) mouse model. Immune cells were isolated from the mice colons or tumors and assessed by flow cytometry.ResultsOur analysis of human CRC tissue revealed a significant reduction in GPR15+ immune cell frequencies in tumors compared to 'tumor-free' surgical margins. Similarly, our data analysis using The Cancer Genome Atlas (TCGA) indicated that lower GPR15 expression is associated with poor survival in human colon cancer. In the AOM/DSS colitis-associated colon cancer model, we observed increased colonic polyps and lower survival in Gpr15 +-KO compared to Gpr15-Het mice. Analysis of immune cell infiltrates in the colonic polyps showed significantly decreased CD8+ T cells and increased IL-17+ CD4+ and IL-17+ CD8+ T cells in Gpr15-KO than in Het mice. Consistent with a protective role of GPR15, administration of GPR15L to established tumors in the MC38-CRC model increased CD45+ cell infiltration, enhanced TNFa expression on CD4+ and CD8+ T cells at the tumor site and dramatically reduced tumor burden.DiscussionOur findings highlight an important, unidentified role of the GPR15-GPR15L axis in promoting a tumor-suppressive immune microenvironment and unveils a novel, colon-specific therapeutic target for CRC.

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Colon cancer and the immune system: the role of tumor invading T cells.

Publications

Colon cancer and the immune system: the role of tumor invading T cells.

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