Abstract
BackgroundT lymphocytes exert important homeostatic functions in the healthy intestinal mucosa, whereas in case of colorectal cancer (CRC), infiltration of T lymphocytes into the tumor is crucial for an effective anti-tumor immune response. In both situations, the recruitment mechanisms of T lymphocytes into the tissues are essential for the immunological functions deciding the outcome. The recruitment of T lymphocytes is largely dependent on their expression of various chemokine receptors. The aim of this study was to identify potential chemokine receptors involved in the recruitment of T lymphocytes to normal human colonic mucosa and to CRC tissue, respectively, by examining the expression of 16 different chemokine receptors on T lymphocytes isolated from these tissues.MethodsTissues were collected from patients undergoing bowel resection for CRC. Lymphocytes were isolated through enzymatic tissue degradation of CRC tissue and nearby located unaffected mucosa, respectively. The expression of a broad panel of chemokine receptors on the freshly isolated T lymphocytes was examined by flow cytometry.ResultsIn the normal colonic mucosa, the frequencies of cells expressing CCR2, CCR4, CXCR3, and CXCR6 differed significantly between CD4+ and CD8+ T lymphocytes, suggesting that the molecular mechanisms mediating T lymphocyte recruitment to the gut differ between CD4+ and CD8+ T lymphocytes. In CRC, the frequencies of cells expressing CCR2 and CXCR5 were significantly lower in both the CD4+ and CD8+ T lymphocyte populations compared to unaffected colonic mucosa, and the frequency of CCR9+ cytotoxic T lymphocytes was significantly decreased in CRC tissue.ConclusionsWith regard to the normal gut mucosa, the results suggest that the molecular mechanisms mediating T lymphocyte recruitment differ between CD4+ and CD8+ T lymphocytes, which are important for understanding gut homeostasis. Importantly, T lymphocytes from CRC compared to normal colonic tissue displayed a distinct chemokine receptor expression profile, suggesting that mechanisms for recruitment of T lymphocytes to CRC tissue are skewed compared to normal colonic mucosa. Understanding these mechanisms could help in developing new strategies in cancer immunotherapy and to optimize already available alternatives such as immune checkpoint inhibitors.
Highlights
T lymphocytes exert important homeostatic functions in the healthy intestinal mucosa, whereas in case of colorectal cancer (CRC), infiltration of T lymphocytes into the tumor is crucial for an effective anti-tumor immune response
Colorectal carcinoma tissues were infiltrated by T lymphocytes To examine the expression profile of chemokine receptors on T lymphocytes recruited to unaffected colonic mucosal tissue and colorectal carcinoma (CRC) tissue, we isolated lymphocytes from human CRC specimens and unaffected lamina propria, for flow cytometry analysis
In accordance with the previous studies showing that T lymphocytes infiltrate into tumor tissue (2, 29), our results showed that the mean number of viable lymphocytes, based on trypan blue exclusion, was higher in carcinoma tissues (5.2 × 106 cells/cm2) compared with unaffected tissues (1.2 × 106 cells/cm2)
Summary
T lymphocytes exert important homeostatic functions in the healthy intestinal mucosa, whereas in case of colorectal cancer (CRC), infiltration of T lymphocytes into the tumor is crucial for an effective anti-tumor immune response. Chemokines constitute a large family (48 known human members) of small (7–10 kDa) peptides that are Löfroos et al Eur J Med Res (2017) 22:40 classified according to the position of their conserved cysteine residues into four groups: CXC, CC, C, and CX3C [4, 5]. Based on their function, they are referred to as homeostatic, inflammatory, or both [6]. In cancer biology, chemokines play a role in a number of additional processes, such as tumor cell growth/survival, metastatic spreading, and angiogenesis [11,12,13]
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