Enhanced anti-retroviral cytotoxic T cell response by PD-1 blockade (VIR4P.1015)

Abstract

Abstract LP-BM5 retrovirus induces a complex disease featuring an acquired immunodeficiency syndrome termed murine AIDS (MAIDS) in susceptible strains of mice, such as C57BL/6 (B6). Our lab has previously shown that a cytotoxicT lymphocyte (CTL) response to MAIDS-associated epitopes that are shared by MAIDS-associated terminal B-cell lymphomas can be detected in uninfected, MAIDS-associated tumor cell primed B6 mice. We further confirmed that B6 mice infected with LP-BM5 retrovirus can generate equally robust anti-MAIDS tumor CTLs compared to the B6 mice primed with tumor cells. To determine if the anti-tumor CD8 T-cell responses can be enhanced by interrupting the down-regulatory PD-1 pathway specifically in the CD8 T-cell compartment, thus to treat MAIDS-associated B-cell lymphomas, we determined whether adoptive transfer of PD-1KO CD8 T cells with or without total CD4 T cells, was able to protect Rag-1KO mice from B6-1710 tumor challenge. Rag-1KO recipients that received B6.PD-1KO.CD8 T cells showed delayed tumor growth following B6-1710 tumor challenge compared to Rag-1KO mice that received equal numbers of w.t B6.CD8 T cells. This enhanced anti-tumor activity was similar to what was observed in mice that received combined PD-1 blockade in CD8 T cell compartment and depletion of CD4 T regulatory cells. Our data indicate that anti-tumor CD8 T cell response can be increased by interrupting the down-regulatory, CD8 T-cell mediated PD-1 pathway.