Manipulation of T cell response to tumors by targeting on costimulatory pathway

T cells require at least two signals to be fully activated: one is generated by interactions between antigenspecific receptor on T cells and peptide-MHC complexes on tumor cells and second signal is delivered by costimulatory molecules on antigen presenting cells to their counter-receptor on T cells. We demonstrated previously that expression of T cell costimulatory molecule B7-1, a counterreceptor for CD28, on tumors led to tumor regression in syngeneic mice. We have used retrovirus to transfer B7-1 into a variety of murine tumor lines to examine their ability to stimulate CTL in vivo and in vitro. Expression of B7 results in increased immunogenicity in immunogenic, but not poorly-immunogenic tumors, suggesting a deficiency of tumor cells on antigen presentation. We analyze tumor epitopes associated with MHC molecules by HPLC combining with specific CTL clones and the results indicate that many non-immunodominant epitopes do not normally induce a response unless B7 costimulation is provided. Furthermore, increased T cell receptor signaling, such as co-expression of CD2 ligand with B7-1, can convert some poorly-immunogenic tumours to become immunogenic. Our results indicate that deficiency on antigenic signaling in many tumors could be a quantitative phenomenon. Induction of T cell immunity by targeting on both antigen receptor and costimulatory pathway thus may be useful for cancer treatment.