Enhancement of T-cell–Mediated Antitumor Response: Angiostatic Adjuvant to Immunotherapy against Cancer

Abstract

Purpose Tumor-released pro-angiogenic factors suppress endothelial adhesion molecule (EAM) expression and prevent leukocyte extravasation into the tumor. This is one reason why immunotherapy has met with limited success in the clinic. We hypothesized that overcoming EAM suppression with angiogenesis inhibitors would increase leukocyte extravasation and subsequently enhance the effectiveness of cellular immunotherapy. Experimental Design Intravital microscopy, multiple-color flow cytometry, immunohistochemistry, and various tumor mouse (normal and T cell-deficient) models were used to investigate the temporal dynamics of cellular and molecular events that occur in the tumor microenvironment during tumor progression and angiostatic intervention. Results We report that while EAM levels and T cell infiltration are highly attenuated early on in tumor growth, angiostatic therapy modulates these effects. In tumor models with normal and T cell-deficient mice, we demonstrate the active involvement of the adaptive immune system in cancer, and differentiate anti-angiogenic effects from anti-angiogenic-mediated enhancement of immuno-extravasation. Our results indicate that a compromised immune response in tumors can be obviated by the use of anti-angiogenic agents. Lastly, with adoptive transfer studies in mice, we demonstrate that a phased combination of angiostatic therapy and T cell transfer significantly (P<0.0013) improves tumor growth inhibition. Conclusions This research contributes to understanding the cellular mechanism of action of angiostatic agents and the immune response within the tumor microenvironment, in particular as a consequence of the temporal dynamics of EAM levels. Moreover, our results suggest that adjuvant therapy with angiogenesis inhibitors holds promise for cellular immunotherapy in the clinic.

The apelin/APJ system induces maturation of the tumor vasculature and improves the efficiency of immune therapy

“…This antitumor effect was attributed to dramatic infiltration of DC-activated iNKT cells and subsequent induction of apoptosis in the tumor cells. It was recently reported that inhibition of angiogenesis lead to normalized endothelial adhesion molecule levels and improves tumor growth inhibition by promoting leukocyte extravasation (Dings et al, 2011). Upregulation of VCAM1 expression was also induced in the endothelium of apelin-expressing tumor, and it would promote iNKT cell infiltration.…”

Targeted vaccination against the bevacizumab binding site on VEGF using 3D-structured peptides elicits efficient antitumor activity

“…Accordingly, we included 5 linear (9-13) peptides and 20 different side-chain cyclized peptides (14)(15)(16)(17)(18)(19)(20)(21)(22)(23)(24)(25)(26)(27)(28)(29)(30)(31)(32)(33) covering this region ( Fig. 1D and SI Appendix, Table S3).…”

“…Angiogenic growth factors contribute to immune suppression by down-regulation of endothelial adhesion molecules (12)(13)(14), inhibition of dendritic cell maturation (15), and attraction and proliferation of immunosuppressive cells (16,17). Conversely, antiangiogenic drugs can help reverse the immunosuppressive state in cancer patients (14,18,19). Therefore, an angiostatic vaccination approach against VEGF can potentially inhibit tumor growth via multiple mechanisms (20).…”

Functionalized calix[4]arenes as potential therapeutic agents

“…Calix [4]arene 0118 (Scheme 4) is a proven potent antiangiogenic agent that effectively inhibits tumor growth in preclinical studies and is presently under investigation in a phase-I clinical trials. [70][71][72] Recently, Lappchen et al [73] synthesized close mimetics of calixarene 0118 of the types 8 and 9 (Scheme 4) and evaluated their cytotoxic properties. All the newly synthesized analogs were not only proved to be equipotent to calixarene 0118, but some of them also inhibited human umbilical vein endothelial cells (HUVEC) and MA148 ovarian carcinoma cell growth nearly 4-and 10-fold more effectively, which is a straightforward evidence of the potential of this class of compounds in anti-angiogenic…”