SELF-ANTIGENS EXPRESSED BY SOLID TUMORS DO NOT EFFICIENTLY STIMULATE NAIVE OR ACTIVATED T-CELLS - IMPLICATIONS FOR IMMUNOTHERAPY

Induction and maintenance of cytotoxic T lymphocyte (CTL) activity spe cific for a primary endogenous tumor was investigated in vivo. The sim ian virus 40 T antigen (Tag) expressed under the control of the rat in sulin promoter (RIP) induced pancreatic beta-cell tumors producing ins ulin, causing progressive hypoglycemia. As an endogenous tumor antigen , the lymphocytic choriomeningitis virus (LCMV) glycoprotein (GP) was introduced also under the control of the RIP. No significant spontaneo us CTL activation against GP was observed. However, LCMV infection ind uced an antitumor CTL response which efficiently reduced the tumor mas s, resulting in temporarily normalized blood glucose levels and prolon ged survival of double transgenic RIP(GP X Tag2) mice (137 +/- 18 d) a s opposed to control RIP-Tag2 mice (88 +/- 8 d). Surprisingly, the tum or-specific CTL response was not sustained despite the facts that the tumor cells continued to express MHC class I and LCMV-GP-specific CTLs were present and not tolerized. Subsequent adoptive transfer of virus activated spleen cells into RIP(GP X Tag2) mice further prolonged sur vival (168 +/- 11 d), demonstrating continued expression of the LCMV-G P turner antigen and MHC class I. The data show that the tumor did not spontaneously induce or maintain an activated CTL response, revealing a profound lack of immunogenicity in vivo. Therefore, repetitive immu nizations are necessary for prolonged antitumor immunotherapy. In addi tion, the data suggest that the risk for induction of chronic autoimmu ne diseases is limited, which may encourage immunotherapy against anti gens selectively but not exclusively expressed by the tumor.