RESISTANCE TO TUMOR-NECROSIS-FACTOR AND CYTOTOXIC T-CELL UNRESPONSIVENESS AS STRATEGIES OF TUMOR-CELLS TO EVADE IMMUNOSURVEILLANCE (REVIEW)

We have been focusing on the study of the molecular basis of tumor res istance to TNF as well as the cytotoxic function of tumor infiltrating lymphocytes specific to renal cell carcinoma in an attempt to elucida te further the tumor/immune system conflict. We have investigated the relationship between acquisition of tumor resistance to TNF and the ex pression of the proto-oncogenes bcl-2, Bax and c-myc known to play a r ole in the control of the induction of programmed cell death. Our data indicate that while bcl-2 and Bar expression do not appear to be asso ciated with the regulation of cell susceptibility to the cytotoxic act ion of TNF, a constitutive high expression of c-myc correlates with th e occurrence of TNF resistance in our cell model. Analysis of TCR dive rsity in TIL represents one way to characterize the in situ immune res ponse. Using newly developed PCR based methodology, we evidenced a hig hly diverse usage of TCR V gene segments in 5 out of 6 renal cell carc inoma (RCC). Strinkingly, one of 6 tumors displayed a skewed TCR reper toire with V beta 4 transcript representing 25% of the TCR signals. Cl onality of the tumor overexpressed transcripts was demonstrated by CDR 3 size distribution analysis and T cell expansions were specifically d etected at the tumor site. In order to analyze the functional activity of these in vivo expanded T cells, tumor specific T cell line and few CTL clones were generated in vitro. CDR3 size analysis demonstrated t hat these effecters were indeed present at the tumor site although the y did not correspond to the highest in vivo expanded subsets. These re sults are discussed with the recently described tumor associated antig ens characterized on human tumors.