Analysis of T-cell immune response in renal cell carcinoma: Polarization to type 1-like differentiation pattern, clonal T-cell expansion and tumor-specific cytotoxicity

We assessed the naturally occurring T-cell immune response in primary renal cell carcinoma (RCC) tumors from 12 unselected patients. A predominance of CD3⁺ T-cell receptor (TCR)α/β⁺ T cells was observed in tumor-infiltrating lymphocytes (TILs), in contrast with peripheral blood lymphopenia found in some patients. Activation antigen expression on TILs revealed an imbalance in the activation status, with a significant percentage of CD69⁺ and HLA-DR⁺ and a low percentage of CD25⁺ and CD71⁺ TILs. The lymphocyte activation gene-3 (LAG-3) was detected in some TIL subpopulations and especially in one patient in whom TILs were predominantly TCRα/β⁺CD8⁺DR⁺LAG-3⁺. In addition, we found that RCC TILs are polarized to a global type I -like (Th1/Tc1) differentiation pattern (strong secretion of interferon-γ and interleukin-2 (IL-2) following CD3/TCR crosslinking) but are under the influence of the down-modulatory cytokines IL-6 (secreted by tumor cells) and IL-10, within the tumor microenvironment. In 3 of 5 patients, clonal T-cell expansion at the tumor site was found for several Vβ specificities, suggesting that in situ stimulation of specific clonotypes in response to potential tumor antigens is a frequent event in RCC. Furthermore, in one patient, selective intratumor amplification of a Vβ1 subpopulation (5% of TCR α/β⁺ cells) corresponding to 2 distinct Vβ1-Jβ1.6 and Vβ1-Jβ2.3 tumor-specific MHC class I-restricted cytotoxic T lymphocytes supports the view that discrete T-cell subsets contribute readily to in situ immunosurveillance.