Therapeutic antitumor potential of endoglin-based DNA vaccine combined with immunomodulatory agents

Abstract

Therapy targeting tumor blood vessels ought to inhibit tumor growth. However, tumors become refractory to antiangiogenic drugs. Therefore, therapeutic solutions should be sought to address cellular resistance to antiangiogenic therapy. In this regard, reversal of the proangiogenic and immunosuppressive phenotype of cancer cells, and the shift of the tumor microenvironment towards more antiangiogenic and immune-stimulating phenotype may hold some promise. In our study, we sought to validate the effects of a combination therapy aimed at reducing tumor blood vessels, coupled with the abrogation of the immunosuppressive state. To achieve this, we developed an oral DNA vaccine against endoglin. This antigen was carried by an attenuated Salmonella Typhimurium and applied before or after tumor cell inoculation into immunocompetent mice. Our results show that this DNA vaccine effectively inhibited tumor growth, in both the prophylactic and therapeutic settings. It also activated both specific and nonspecific immune responses in immunized mice. Activated cytotoxic T-lymphocytes were directed specifically against endothelial and tumor cells overexpressing endoglin. The DNA vaccine inhibited angiogenesis but did not affect wound healing. In combination with interleukin-12-mediated gene therapy, or with cyclophosphamide administration, the DNA vaccine resulted in reduced microvessel density and lowered the level of T reg lymphocytes in the experimental tumors. This effectively inhibited tumor growth and prolonged survival of the treated animals. Polarization of tumor milieu, from proangiogenic and immunosuppressive, towards an immunostimulatory and antiangiogenic profile represents a promising avenue in anticancer therapy.

Tumor Blood Vessels and Vasculogenic Mimicry – Current Knowledge and Searching for New Cellular/Molecular Targets of Anti-Angiogenic Therapy

“…However, in breast, oesophagus, or prostate cancer, endoglin is responsible for limiting of tumor cell migration and metastasis. In this situation, the decrease of CD105 expression can be very negative [43]. The results of other effective immunotherapy were also published [44].…”

“…Tumor cells of different types of cancer may also demonstrate CD105 expression [43]. The discovery of tumor cells ability to endoglin expression was unexpected, and now this antigen is regarded as a very important therapeutic target.…”

“…However, the study on oesophagus cancer provided that CD105 expression is low [88]. The effect of endoglin is not the same in different types of tumors [43].…”

“…Gene therapy with oral DNA vaccine focused on CD105 is an important component in fight against tumor vascularization [43,47]. Attenuated Salmonella bacteria, with CD105 gene introduced into their genomes, were used to construct the vaccine.…”

Optimizing the restored chemotactic behavior of anticancer agent Salmonella enterica serovar Typhimurium VNP20009

“…Several strains of S. Typhimurium have been constructed for the purpose of tumor targeting and chemotherapy delivery, most mentionable being: A1 (Zhao et al, 2005)/A1-R Hiroshima et al, 2013;Hoffman, 2016;Hiroshima et al, 2014;Yano et al, 2014;Murakami et al, 2016;Kawaguchi et al, 2016), BRD509/BRD509E (Yoon et al, 2014;al-Ramadi et al, 2009), χ4550 (Saltzman et al, 1996), CRC2631 (Eisenstark et al, 2007), ΔppGpp (Jiang et al, 2013;Kim et al, 2015;Nguyen et al, 2010), LH340 (Zhang et al, 2007;VanCott et al, 1998;Jia et al, 2012), LVR01 (Grille et al, 2014), MvP728 (Manuel et al, 2011;Xu et al, 2014;Xiong et al, 2010), RE88 (Xiang et al, 2005;Lee et al, 2006;Qian et al, 2011), SA186 (Chirullo et al, 2015), SB824 (Roider et al, 2011), SL3261 (Lin et al, 2012;Ye et al, 2013), SL7207 (Jarosz et al, 2013;Li et al, 2013;Shi et al, 2016;Berger et al, 2013), YB1 (Li et al, 2017;Yu et al, 2015), and VNP20009 . VNP20009 was created by Low et al ) from strain 14028s through selection for hyperinvasion by chemical/UV mutagenesis.…”