The progressive conversion of normal cells into cancer cells is characterized by the acquisition of eight hallmarks. Among these criteria, the capability of the cancer cell to avoid the immune destruction is found. Thus, tumors develop mechanisms to become invisible to the immune system, such as the induction of immunosuppressive cells which are able to inhibit the development of an efficient immune response. Molecules produced in the tumor microenvironment are involved in the occurrence of an immunosuppressive microenvironment. Recently, it has been shown that Vascular Endothelial Growth Factor -A (VEGF-A) exhibits immunosuppressive properties in addition to its proangiogenic activities. VEGF-A can induce the accumulation of immature dendritic cells, myeloid derived suppressor cells, regulatory T cells and inhibit the migration of T lymphocytes to the tumor. Other proangiogenic factors such as Placental Growth Factor (PlGF) could also participate in tumor-induced immunosuppression, but only few works have been performed on this point. Here, we review the impact of proangiogenic factors (especially VEGF-A) on immune cells. Anti-angiogenic molecules, which target VEGF-A/VEGFR axis, have been developed in the last decades and are commonly used to treat cancer patients. These drugs have anti-angiogenic properties but can also counteract the tumor-induced immunosuppression. Based on these immunomodulatory properties, anti-angiogenic molecules could be efficiently associated with immunotherapeutic strategies in preclinical models. These combinations are currently under investigation in cancer patients.

Vascular endothelial growth factor A is known to play a central role in tumor angiogenesis. Several studies showed that VEGF-A is also an immunosuppressive factor. In tumor-bearing hosts, VEGF-A can modulate immune cells (DC, MDSC, TAM) to induce the accumulation of regulatory T-cells while simultaneously inhibiting T-cell functions. Furthermore, VEGFR-2 expression on activated T-cells and FoxP3^highregulatory T-cells also allow a direct effect of VEGF-A. Anti-angiogenic agents targeting VEGF-A/VEGFR contribute to limit tumor-induced immunosuppression. Based on interesting preclinical studies, many clinical trials have been conducted to investigate the efficacy of anti-VEGF-A/VEGFR treatments combined with immune checkpoint blockade leading to the approvement of these associations in different tumor locations. In this review, we focus on the impact of VEGF-A on immune cells especially regulatory and effector T-cells and different therapeutic strategies to restore an antitumor immunity.

Considering the high importance of immune surveillance and immune escape in the evolution of cancer, the development of immunotherapeutic strategies has become a major field of research in recent decades. The considerable therapeutic breakthrough observed when targeting inhibitory immune checkpoint molecules has highlighted the need to find approaches enabling the induction and proper activation of an immune response against cancer. In this context, therapeutic vaccination, which can induce a specific immune response against tumor antigens, is an important approach to consider. However, this strategy has its advantages and limits. Considering its low clinical efficacy, approaches combining therapeutic cancer vaccine strategies with other immunotherapies or targeted therapies have been emphasized. This review will list different cancer vaccines, with an emphasis on their targets. We highlight the results and limits of vaccine strategies and then describe strategies that combine therapeutic vaccines and antiangiogenic therapies or immune checkpoint blockade. Antiangiogenic therapies and immune checkpoint blockade are of proven clinical efficacy for some indications, but are limited by toxicity and the development of resistance. Their combination with therapeutic vaccines could be a way to improve therapeutic outcome by specifically stimulating the immune system and considering a global approach to tumor microenvironment remodeling.

Some of the anti-angiogenic agents currently used to treat solid malignancies have effects on tumor endothelial cells as well as on immune cells. We have recently demonstrated that targeting the va...

The endothelium is nowadays described as an entire organ that regulates various processes: vascular tone, coagulation, inflammation, and immune cell trafficking, depending on the vascular site and its specific microenvironment as well as on endothelial cell-intrinsic mechanisms like epigenetic changes. In this review, we will focus on the control of the adaptive immune response by the tumor vasculature. In physiological conditions, the endothelium acts as a barrier regulating cell trafficking by specific expression of adhesion molecules enabling adhesion of immune cells on the vessel, and subsequent extravasation. This process is also dependent on chemokine and integrin expression, and on the type of junctions defining the permeability of the endothelium. Endothelial cells can also regulate immune cell activation. In fact, the endothelial layer can constitute immunological synapses due to its close interactions with immune cells, and the delivery of co-stimulatory or co-inhibitory signals. In tumor conditions, the vasculature is characterized by abnormal vessel structure and permeability, and by specific phenotype of endothelial cells. All these abnormalities lead to a modulation of intratumoral immune responses and contribute to the development of intratumoral immunosuppression, which is a major mechanism for promoting the development, progression and treatment resistance of tumors. The in-depth analysis of these various abnormalities will help defining novel targets for the development of antitumoral treatments. Furthermore, eventual changes of the endothelial cell phenotype identified by plasma biomarkers could secondarily be selected to monitor treatment efficacy.