In the last decades a new class of therapeutic drugs have been developed that block tumor angiogenesis. These antiangiogenic molecules, which target VEGF or VEGFR, PDGFR, and c-kit, can act not only on endothelial cells but also on immune cells. Some antiangiogenic molecules inhibit the development of immunosuppressive mechanisms developed by the tumors to escape the immune system (such as regulatory T cells, myeloid-derived suppressor cells, and immunosuppressive cytokines). These immunomodulatory effects must be characterized in detail to enable a better prescription of these treatments. In this paper we will focus on the impact of anti-angiogenic drugs on immunosuppression and their potential combination with immunotherapeutic strategies. Interestingly, immune parameters or their modulation during treatment could serve as potential biomarkers of response or resistance to anti-angiogenic therapies. 1. Introduction In 2000, Hanahan and Weinberg defined 6 hallmark criteria of cancer. Six points constitute these hallmarks: sustaining proliferative signaling, evading growth suppressors, resisting cell death, enabling replicative immortality, inducing angiogenesis, and activating invasion and metastasis [1]. In 2011, these criteria have been revisited and 2 emerging criteria have been added: deregulating cellular energetics and avoiding immune destruction [2]. Thus cancer cells have to bypass the surveillance of the immune system that normally restricts the development of tumors. The role of immunosurveillance in cancer has been highlighted by experimental and clinical studies. Mice deficient for lymphocytes or IFN type I signaling are more susceptible to cancer development than wild-type mice [3]. In humans, tumor incidence in immunocompromised patients (transplanted patients or HIV patients) is enhanced [4, 5]. Conversely, tumor infiltration by T or NK cells is correlated with a good prognosis in colorectal or ovarian cancer patients [6–8]. Recently, different works have shown that the immune system could play a role in the antitumor effect of conventional cancer therapies [9]. The immune system could be involved in two different ways. First, conventional cancer therapies can directly act on tumor cells and induce an immunogenic cell death. Thus, conventional cancer therapies trigger tumor cell death and release of apoptotic bodies that could be uptaken and presented by dendritic cells [9]. On the other hand, conventional cancer therapies can modulate tumor microenvironment by inhibiting immunosuppressive mechanisms induced by the tumor or by stimulating
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