T-CELL CO-STIMULATION BY THE CD28 LIGAND B7 IS INVOLVED IN THE IMMUNE-RESPONSE LEADING TO REJECTION OF A SPONTANEOUSLY REGRESSIVE TUMOR

Cell variants from experimental tumors may lose their tumorigenicity o r give rise to tumors that regress after a short period of progression in immunocompetent syngeneic animals. Rejection of these tumor cells is often T-cell-dependent. It has recently been reported that, besides the specific signal delivered through the clonogenic receptor, T-cell activation requires a co-stimulatory signal, delivered through its CD 28 receptor by B7-1 and/or B7-2 molecules expressed at the surface of the antigen-presenting cells. CTLA41g, a fusion molecule that specific ally inhibits B7-1 and B7-2 binding to their receptor on T cells, was used to investigate the role of B7 in the spontaneous regression of th e tumors induced in syngeneic rats by REGb cells, a regressor cell lin e established from a chemically induced colon carcinoma. When rats rec eived either or 3 CTLA41g injections, REGb tumors grew 3 or 7 times la rger than in control animals, respectively. However, in most animals, single or repeated CTLA41g injections delayed rather than suppressed R EGb tumor rejection. Antibodies to CTLA41g: appeared in treated rats a nd could explain this transient effect. Neither REGb cells nor freshly isolated MHC class-II+ antigen-presenting cells infiltrating REGb tum ors expressed B7, establishing that the target of CTLA41g was not loca ted inside the tumor. In contrast, MHC class-II+ B7(+) accessory cells were found in the REGb tumor-draining lymph nodes, suggesting that ly mphoid tissue, rather than the tumor itself, was the site of tumor-ant igen presentation to tumor-specific T cells. These results establish t he role of the B7/CD28 co-stimulation pathway in the control of a spon taneously regressive tumor. (C) 1996 Wiley-Liss, Inc.