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 antigen-specific receptor on T cell 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.
Chen
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Laboratory of Tumour Immunology, Bristol-Myers Squibb Pharmaceutical Research Institute, Seattle, Washington 98121, USA.
D000818:Animals; D018122:B7-1 Antigen / Q000096:biosynthesis*; D018106:CD28 Antigens / Q000096:biosynthesis*; D007167:Immunotherapy; D008285:Major Histocompatibility Complex; D051379:Mice; D009368:Neoplasm Transplantation; D012513:Sarcoma, Experimental / Q000276:immunology* / Q000628:therapy*; D015398:Signal Transduction; D013601:T-Lymphocytes / Q000276:immunology*; D013602:T-Lymphocytes, Cytotoxic / Q000276:immunology*; D014162:Transfection; D014185:Transplantation, Isogeneic
D018122:B7-1 Antigen; D018106:CD28 Antigens