Chemokine Receptor Expression on T Cells Is Modulated by CAFs and Chemokines Affect the Spatial Distribution of T Cells in Pancreatic Tumors

SIMPLE SUMMARY: The infiltration of T cells in pancreatic tumors has been correlated with better overall survival. However, the dense desmoplastic stroma, mainly composed by cancer-associated fibroblasts (CAFs), can sequester the T cells in the stroma preventing them from reaching the tumor nests. Chemokines are small molecules capable of directing T cell migration. Here, we explored whether CAFs could modulate the expression of chemokine receptors on T cells and examined if the spatial distribution of T cells within tumors was correlated to chemokine secretion patterns. Overall, we found that CXCR3 ligands was associated with an increased number of T cells in tumor rich areas and that CAFs downregulated the expression of CXCR3 on T cells. Understanding the mechanisms by which T cells are prevented from reaching the tumor nests is of great importance for the development of novel targeting therapies. ABSTRACT: The accumulation of T cells is associated with a better prognosis in pancreatic cancer. However, the immunosuppressive tumor microenvironment, largely composed by cancer-associated fibroblasts (CAFs), can prevent T cells from reaching the tumor nests. We examined how human CAFs modulated chemokine receptors known to be associated with T cell trafficking, CXCR3 and CCR5, and T cell exclusion, CXCR4. CAFs decreased the expression of CXCR3 and CCR5 but increased CXCR4 expression in both 2D and 3D cultures, affecting the migratory capacity of T cells towards CXCL10. An immunohistochemistry analysis showed that very few T cells were found in the tumor nests. Within the stroma, CD8(+) T cells were localized more distantly from the malignant cells whereas CD4(+) T cells were more equally distributed. Tumor tissues with a high production of chemokines were associated with less T cell infiltration when the whole tissue was analyzed. However, when the spatial localization of CD8(+) T cells within the tissue was taken into account, levels of CXCR3 ligands and the CCR5 ligand CCL8 showed a positive association with a high relative T cell infiltration in tumor-rich areas. Thus, CXCR3 ligands could mediate T cell trafficking but CAFs could prevent T cells from reaching the malignant cells.