Magnitudes of cytotoxic T-lymphocyte infiltration and secretion of their targeting chemokines are bimodally distributed among a population of colorectal tumor microenvironments.
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Zumwalt, Timothy J., 1982-
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T-cell infiltration varies among colorectal tumors and directly impacts patient survival. Chemoattraction and infiltration of CD8⁺ T-cells are mediated by surface chemokine receptors CXCR3 and CCR5, and are associated with favorable prognosis. Transcriptional expression of these receptors’ cognate chemokines, as well as other inflammation-associated chemokines, correlate with prolonged disease-free survival (DFS). These findings, however, were derived from paraffin embedded tissues, thus little is known about the pattern of secreted T-cell targeting chemokines from colorectal tumors. Therefore, this investigation aimed to determine the secretion pattern of chemokines associated with DFS from immediately excised live tumor tissues. Our results demonstrate the first real functional analysis of chemokine activity in colorectal tumors beyond immunohistochemistry and real-time PCR. Forty-four colorectal tumors were procured immediately after surgery and categorized by transcriptional expression of two T-cell marker genes that represent the magnitude of type-1 T-cell activity. Tumors that more highly co-expressed IFNG and TBX21 consequently have a higher frequency of infiltrating GzmB⁺ CTLs and IFN-γ⁺ CD4⁺ helper T-cells and transcribe a unique pattern of DFS-associated chemokines when compared to normal mucosa. High co-expression of IFNG and TBX21 was bimodally distributed across the tumors collected. Tumors with higher co-expression more strongly secreted two DFS-associated chemokines, CXCR3 ligand, CXCL10 and CCR5 ligand, CCL5. Additional results demonstrate that tumors with higher co-expression are proportionally skewed towards early TMN stages and with mismatch repair-deficiency, confirming that infiltration of CD8⁺ T-cells are associated with early TNM stages and lack of metastasis. Secreted chemokines were detected using a novel immunoassay that may have implications for future development of immunopotentiating treatments in cancer.