DEFECTIVE GRANZYME-B GENE-EXPRESSION AND LYTIC RESPONSE IN T-LYMPHOCYTES INFILTRATING HUMAN RENAL-CELL CARCINOMA

Granzyme B is a protein thought to play a pivotal role in the cytolyti c functions of T cells. In view of this, the inducibility of this gene in freshly isolated T cells (T-TILs) infiltrating human renal cell ca rcinoma (RCC) in vitro was examined by using the reverse transcriptase -polymerase chain reaction (RT-PCR). A reduction in granzyme B messeng er RNA (mRNA) expression in stimulated T-TILs from five of nine patien ts with RCC compared with autologous peripheral blood T cells was note d. The reduced expression was observed after multiple stimuli includin g anti-CD3 antibody, interleukin-2 (IL-2), and phytohemagglutinin (PHA ). Because CD8(+) T cells represent the predominant cytotoxic populati on, the ability of this cell population to express granzyme B mRNA aft er stimulation also was examined. when compared with CD8(+) peripheral blood lymphocytes (T-PBLs) from patients with RCC and normal donors, the induction of granzyme B mRNA was reduced in CD8(+) T-TILs. CD8(+) T-TILs also had lower non-major histocompatibility complex (MHC)-restr icted cytotoxic activity than did CD8(+) T-PBLs against both Daudi cel ls and allogeneic RCC cell lines. These results show that in a subset of patients with RCC, depressed lytic activity of CD8(+) TILs compared with CD8(+) PBLs is present. Reduced granzyme B mRNA expression also was noted in selected patients.