Direct and Indirect Modulation of T Cells by VEGF-A Counteracted by Anti-Angiogenic Treatment.

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 FoxP3high regulatory 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.

Bourhis M ，Palle J ，Galy-Fauroux I ，Terme M ... -  《Frontiers in Immunology》

Augmenting Anticancer Immunity Through Combined Targeting of Angiogenic and PD-1/PD-L1 Pathways: Challenges and Opportunities.

Cancer immunotherapy (CIT) with antibodies targeting the programmed cell death 1 protein (PD-1)/programmed cell death 1 ligand 1 (PD-L1) axis have changed the standard of care in multiple cancers. However, durable antitumor responses have been observed in only a minority of patients, indicating the presence of other inhibitory mechanisms that act to restrain anticancer immunity. Therefore, new therapeutic strategies targeted against other immune suppressive mechanisms are needed to enhance anticancer immunity and maximize the clinical benefit of CIT in patients who are resistant to immune checkpoint inhibition. Preclinical and clinical studies have identified abnormalities in the tumor microenvironment (TME) that can negatively impact the efficacy of PD-1/PD-L1 blockade. Angiogenic factors such as vascular endothelial growth factor (VEGF) drive immunosuppression in the TME by inducing vascular abnormalities, suppressing antigen presentation and immune effector cells, or augmenting the immune suppressive activity of regulatory T cells, myeloid-derived suppressor cells, and tumor-associated macrophages. In turn, immunosuppressive cells can drive angiogenesis, thereby creating a vicious cycle of suppressed antitumor immunity. VEGF-mediated immune suppression in the TME and its negative impact on the efficacy of CIT provide a therapeutic rationale to combine PD-1/PD-L1 antibodies with anti-VEGF drugs in order to normalize the TME. A multitude of clinical trials have been initiated to evaluate combinations of a PD-1/PD-L1 antibody with an anti-VEGF in a variety of cancers. Recently, the positive results from five Phase III studies in non-small cell lung cancer (adenocarcinoma), renal cell carcinoma, and hepatocellular carcinoma have shown that combinations of PD-1/PD-L1 antibodies and anti-VEGF agents significantly improved clinical outcomes compared with respective standards of care. Such combinations have been approved by health authorities and are now standard treatment options for renal cell carcinoma, non-small cell lung cancer, and hepatocellular carcinoma. A plethora of other randomized studies of similar combinations are currently ongoing. Here, we discuss the principle mechanisms of VEGF-mediated immunosuppression studied in preclinical models or as part of translational clinical studies. We also discuss data from recently reported randomized clinical trials. Finally, we discuss how these concepts and approaches can be further incorporated into clinical practice to improve immunotherapy outcomes for patients with cancer.

Hack SP ，Zhu AX ，Wang Y 《Frontiers in Immunology》

The Intersection between Tumor Angiogenesis and Immune Suppression.

Both immune checkpoint inhibitors (ICI) and antiangiogenesis agents have changed the landscape of cancer treatment in the modern era. While antiangiogenesis agents have demonstrated activities in tumors with high vascularization, including renal cell carcinoma and colorectal cancer, the effect of ICIs has been seen mainly in immunologically recognized tumors, with highly immune-infiltrative lymphocytes. The main challenge in the drug development of ICIs is moving their activities to noninflamed tumors and overcoming resistance that is driven, in part, by the immune-suppressive microenvironment. Angiogenesis factors drive immune suppression by directly suppressing the antigen-presenting cells as well as immune effector cells or through augmenting the effect of regulatory T cells (Treg), myeloid-derived suppressor cells (MDSC), and tumor-associated macrophages (TAM). Those suppressive immune cells can also drive angiogenesis, creating a vicious cycle of impaired immune activation. The combination of bevacizumab and ipilimumab was the first to show the promising effect of antiangiogenesis and ICIs. A plethora of similar combinations has entered the clinic since then, confirming the promising effects of such approach.

Rahma OE ，Hodi FS 《-》

Vascular Targeting to Increase the Efficiency of Immune Checkpoint Blockade in Cancer.

Georganaki M ，van Hooren L ，Dimberg A 《Frontiers in Immunology》

Combination of anti-angiogenic therapy and immune checkpoint blockade normalizes vascular-immune crosstalk to potentiate cancer immunity.

Lee WS ，Yang H ，Chon HJ ，Kim C ... -  《-》