IFN-GAMMA INDUCIBILITY OF CLASS-II TRANSACTIVATOR IS SPECIFICALLY LACKING IN HUMAN TUMOR LINES - RELEVANCE TO RETINOBLASTOMA PROTEIN RESCUEOF IFN-GAMMA INDUCIBILITY OF THE HLA CLASS-II GENES

We have previously reported that HLA class II induction by IFN-gamma i s rescuable by reconstitution of functional retinoblastoma protein (RE ) in two RB-defective tumour lines: the breast carcinoma line. MDA-468 -S4 (S4) and the non-small cell lung carcinoma line. H2009. To determi ne the range of rumours and tumour types in which RB rescues HLA class II inducibility, we examined another RB-defective tumour line, the re tinoblastoma line, WERI-Rb1. As in the case of S4 and H2009, HLA-DRA a nd -DRB were noninducible by IFN-gamma in WERI-Rb1. However, neither i nducibility of DRA nor DRB mRNA was restored in an RB-positive stable transformant of WERI-Rb1, WLRB-8. While guanylate-binding protein (GBP ) inducibility indicated that the basic IFN-gamma signal transduction pathway remained intact in WERI-Rb1, mRNA for class II transactivator (CIITA), a mediator of the IFN-gamma activation of the HLA class II ge nes and several other genes related to immune function, was not detect able in IFN-gamma-treated WERI-Rb1, indicating that the lack of CIITA expression was responsible, at least in parr, for the inability of RE to rescue HLA class II-inducibility. The HLA class II associated invar iant chain (Ii), the expression of which is also up-regulated by CIITA , was non inducible in WERI-Rb1, consistent with non-inducible CIITA. Also, IFN-gamma failed to activate the DRA, DRB and Ii promoters in WE RT-Rb1. However, exogenous CIITA expression in WERI-Rb1 activated the DRA, DRB and Ii promoter-chloramphinocol acetyltransferase constructs, confirming that CIITA was not induced in WERI-Rb1 and indicating that other proteins required for activation of the class II and Ii promote rs were functional in this cell line. Examination of additional cell l ines for GBP and CIITA induction revealed that a specific lack of the CIITA IFN-gamma response is common in human tumour lines. The possible role of CIITA defects in tumorigenesis is discussed.