Soluble B and T Lymphocyte Attenuator Possesses Antitumor Effects and Facilitates Heat Shock Protein 70 Vaccine-Triggered Antitumor Immunity against a Murine TC-1 Cervical Cancer Model In Vivo

Abstract

B and T lymphocyte attenuator (BTLA)-herpesvirus entry mediator (HVEM) signaling coinhibitory pathway is believed to impair antitumor immune competences. An intriguing unresolved question is whether blockade of BTLA-HVEM guides an effective therapeutic tool against established tumors. To address this issue, we constructed a eukaryotic expression plasmid (psBTLA) that expressed the extracellular domain of murine BTLA (soluble form of BTLA), which could bind HVEM, the ligand of BTLA, and block BTLA-HVEM interactions. The data in this study showed that treatment by injection of psBTLA resulted in down-regulation of IL-10 and TGF-β and promotion of dendritic cell function by increasing the expression of B7-1 and IL-12, but the adaptive antitumor immune responses achieved by psBTLA administration alone were limited and could not eradicate the tumor effectively. Next, we evaluated the immunotherapeutic efficacy and mechanism of combination therapy of heat shock protein 70 (HSP70) vaccine/psBTLA by using murine TC-1 cervical cancer mice as an ectopic tumor model. Our in vivo studies revealed that treatment with HSP70 vaccine alone did not lead to satisfactory tumor growth inhibition, whereas cotreatment with psBTLA significantly improved antitumor immunity and compensated the deficiency of HSP70 vaccine by increasing the expression of Th1 cytokines, IL-2, and IFN-γ and decreasing transcription levels of IL-10, TGF-β, and Foxp3 in the tumor microenvironment. Taken together, our findings indicate that blocking the BTLA-HVEM interaction with sBTLA enhances antitumor efficacy and results in a significant synergistic effect against existent tumor cells in vivo when combined with the HSP70 vaccine.

Prevention of K-Ras- and Pten-mediated intravaginal tumors by treatment with camptothecin-loaded PLGA nanoparticles

“…In the case of cervical cancer, subcutaneous implantations of tumor cells expressing oncogenic HPV proteins are most common [14, 15]. While an ectopic tumor model has some value in studying systemic and intratumoral therapies, it does not permit evaluation of local delivery in the context of the tissue of origin.…”

Heat Shock Proteins (HSPs) Based Anti-Cancer Vaccines

“…This is consistent with the work of Qian et al [83], they have shown that NK cells play a role in a Gp96-based vaccine against myeloma, but that IFN-and both CD4+ and CD8+ T cells are the major effectors in this vaccine model. In a similar way, Han et al [69] reported that the increased antitumor immunity of the Hsp70 vaccine model that they used ( Table 3), was associated with higher expression of Th1 cytokines (IL-2 and IFN-) and decreased transcription of IL-10, TGF-, and Foxp3 in the tumor microenvironment. In a similar way, Han et al [69] reported that the increased antitumor immunity of the Hsp70 vaccine model that they used ( Table 3), was associated with higher expression of Th1 cytokines (IL-2 and IFN-) and decreased transcription of IL-10, TGF-, and Foxp3 in the tumor microenvironment.…”

Is There Still Room for Cancer Vaccines at the Era of Checkpoint Inhibitors

“…A soluble form of BTLA encoded by recombinant adeno-associated virus (AAV) or a DNA plasmid, in combination with an HSP70 vaccine generated a potent antitumor response in the melanoma lung metastasis model in B6 mice and in a lung epithelial tumor [93,94]. …”