The recruitment and role of effector and regulatory T cells in renal cell carcinoma

Abstract

Immunotherapy for renal cell carcinoma (RCC) has yielded some clinical responses. However this approach frequently fails, possibly due to inefficient migration of T-cells to tumour tissue or immunosuppressive mechanisms within the tumour environment. To aid development of T-cell therapy for RCC I investigated how T-cells are recruited to this tumour, which T-cell subsets infiltrate, and how they function.
Analysis of the expression of all 19 chemokine receptors on matched TIL and PBMC demonstrated that CCR5, CXCR3 and CXCR6 were expressed at significantly higher levels on tumour-infiltrating T-cells than memory T-cells in PBMC, suggesting a role for these receptors in recruitment to RCC. Immunohistochemistry showed the corresponding ligands were present in RCC, and transwell assays confirmed the ligands induce migration of TIL. I demonstrated Foxp3\(^+\)CD25\(^{hi}\)CD127\(^{low}\) Tregs were enriched within the tumour, and also expressed high levels of CCR5, CXCR3 and CXCR6, as well as CCR6. They lacked expression of IL-2 and IFN-\(\gamma\) post-stimulation, consistent with a regulatory phenotype. Functional characterisation of Foxp3\(^-\) TIL demonstrated they can function ex vivo, however their high expression of the inhibitory molecule PD-1 may indicate exhaustion in vivo. Double positive CD4\(^+\)CD8\(^+\) T-cells were also enriched in TIL and had a similar functional profile to CD8 T-cells.