Soluble BTLA Possesses Antitumor Effect And Facilitates HSP70 Vaccine Triggered Antitumor Immunity

The interaction between B and T lymphocyte attenuator (BTLA), an inhibitory receptor whose extracellular domain belongs to the immunoglobulin superfamily, and herpesvirus-entry mediator (HVEM), a co-stimulatory tumour-necrosis factor receptor, is unique in that it is the only receptor-ligand interaction that directly bridges these two families of receptors. This interaction has raised many questions about how receptors from two different families could interact and what downstream signalling events might occur as a result of receptor ligation. As we discuss, recent studies show that engagement of HVEM with its endogenous ligand (LIGHT) from the tumour-necrosis factor family induces a powerful immune response, whereas HVEM interactions with BTLA negatively regulate T-cell responses.Blocking BTLA-HVEM interaction augments adaptive immune response which benefits the prevention of tumor. However, whether it is effective as a therapeutic tool against established tumors is not well elucidated. In the present study, we evaluated the efficacy and mechanism of immunotherapy with soluble BTLA derived from psBTLA alone or sBTLA-AAV alone or its combination with HSP70 vaccine. The murine TC-1 cervical cancer served as an ectopic tumor model. The murine B16F10 melanoma served as a metastatic tumor model. The synergistic mechanism of combination therapy was elucidated by detecting the change of gene expression of immunoregulatory factors in tumor microenvironment. The effects of immunotherapy were evaluated by detecting the function of tumor-specific T cells, measuring tumor weight or survival of mice, and H&E staining of tissues. We found local gene transfer by injection of psBTLA alone possessed antitumor effect but limited, whereas, it significantly improve HSP70 vaccine-mediated antitumor immunity. Gene expression detection in tumor microenvironment showed significantly higher transcription activities of Th1 cytokines IL-2 and IFN-γgene and lower level of negative regulatory molecules IL-10, TGF-βand foxp3 in combination therapy group. Moreover, combination therapy could generate stronger memory effect. Taken together, our findings indicate that blocking BTLA-HVEM interaction with sBTLA enhances antitumor efficacy and showed significantly combined effect with HSP70 vaccine against the in vivo existent tumor cells.