Identification of an enriched CD4+ CD8alpha++ CD8beta+ T-cell subset among tumor-infiltrating lymphocytes in human renal cell carcinoma.

Three-color immunofluorescence flow-cytometric analysis of freshly isolated tumor-infiltrating lymphocytes (TIL) from patients with primary renal cell carcinoma (RCC) revealed a unique, not previously described TIL subset with a CD3+ CD4+ CD8alpha++ CD8beta+ phenotype. This subset represented at least 5% of CD3+ TIL in 15 of 21 patients with clear cell RCC, whereas it was not or only marginally represented in patients with papillary RCC or sarcomatoid RCC. In one-third of the patients with clear cell RCC, more than 20% of CD3+ TIL and in one patient more than half of the CD3+ TIL displayed this phenotype. The occurrence of this subset was not associated with pathological stage, tumor diameter, nuclear grade, cytogenetic abnormalities or vascular invasion in this patient cohort. When present, the CD3+ CD4+ CD8alpha++ CD8beta+ subset was detected in similar proportions in tumor tissue and tumor capsula, and it was also detected in adjacent non-tumoral renal tissue, albeit in much lower proportions. Despite strong cell surface expression of various activation markers (CD69, CD54 and HLA-DR), CD3+ CD4+ CD8alpha++ CD8beta+ cells displayed no ex vivo cytolytic activity in an anti-CD3-redirected cytotoxicity assay. In contrast with CD3+ CD4+ CD8- cells from the same tumor sample, they were markedly deficient in IL-2R alpha up-regulation following anti-CD3 triggering. The possibility that these cells represent either anergic cells or a highly specialized effector population with a discrete, as yet undescribed function is discussed.