TUMOR REJECTION REQUIRES A CTLA4 LIGAND PROVIDED BY THE HOST OR EXPRESSED ON THE TUMOR - SUPERIORITY OF B7-1 OVER B7-2 FOR ACTIVE-TUMOR IMMUNIZATION

Although transfection to express any of a multitude of immunomodulator y molecules can lead to the rejection of murine tumors in vivo, it is not clear which of these cofactors are truly important for the inducti on of tumor-specific CTL, Examination of the costimuli used by the hos t immune response during the normal rejection of immunogenic tumors sh ould reveal critical cofactors for CTL differentiation in vivo, The in volvement of a host B7 family costimulator molecule in the rejection o f immunogenic tum(-) variants of the mastocytoma P815 was explored. Re jection of immunogenic P815 variants was prevented by mCTLA4 gamma 3, a fusion protein between the extracellular domain of murine CTLA4 and the Fc portion of a murine IgG3 Ab, indicating the importance of a CTL A4 ligand provided by the host in the rejection of B7(-) tumors, Tumor rejection also was prevented by mCTLA4 gamma 3 in the absence of CD4( +) cells, suggesting that CD8(+) lymphocytes may receive direct costim ulation by B7 in vivo, Finally, although living transfectants of poorl y immunogenic P1.HTR cells expressing B7-1 or B7-2 were equally reject ed by syngeneic mice, if delivered as multiple injections of irradiate d cells, only B7-1 transfectants successfully induced CTL activity and protected against living tumor challenge, Our results indicate that a CTLA4 ligand is normally involved in the generation of CD8(+) CTL aga inst tumor Ag and suggest that immunization with irradiated B7-1-trans fected tumor cells may be superior to immunization with irradiated B7- 2 transfectants as an approach to tumor Ag vaccination in patients.