Role of low nuclear grading of renal carcinoma cells in the functional profile of tumor-infiltrating T cells

Tumor-infiltrating lymphocytes (TILs) from biopsies of 9 selected patients with pT1pN0M0 renal cell carcinoma (RCC) were analyzed at the clonal level for phenotypic distribution, cytokine secretion profile and antitumor cell proliferation and cytotoxicity. T-cell clones generated from RCCs were able to produce higher amounts of interleukin-4 (IL-4) and interferon-gamma (IFN-gamma) than the corresponding clones derived from peripheral blood mononuclear cells, thus suggesting a recruitment into tumors of T cells with peculiar functions. Moreover, CD4+ T-cell clones generated from TILs of nuclear grading 2 (G2)-type RCC patients produced significantly higher amounts of IL-4 and IL-10 and lower amounts of IFN-gamma than the corresponding clones generated from G1-type RCC and 2 renal angiomyolipoma (AML) patients. In addition, T-cell clones generated from lymphocytes infiltrating the peritumoral areas of G2-type, but not those from G1-type, RCC patients produced higher and lower amounts of IL-4 and IFN-gamma, respectively, than the corresponding clones derived from intratumoral T cells of the same patients. The proportion of T-cell clones derived from G2-type tumors and proliferating to autologous tumor cells (ATCs) was significantly lower than that of clones generated from G1-type RCC or AML patients. However, irrespective of their source, they exhibited similar cytokine profiles and produced comparable amounts of IL-4, IL-10 and IFN-gamma. Furthermore, the proportion and the production of both IL-4 and IFN-gamma of G2-type RCC-derived T-cell clones with cytotoxic activity against ATC were significantly lower than those of cytolytic clones generated from AML and G1-type RCCs. The concentrations of IL-4, IL-10 and IFN-gamma produced by the cytolytic clones from G2-type RCC were also lower than those produced by their noncytolytic counterparts obtained from the same patients. These data address the association of the nuclear grading of neoplastic cells with different local tumor-specific T-cell responses in RCC.