The Impact of Angiogenic Growth Factors and Hypoxia on The Antitumor Immune Response

Angiogenesis is a process involved in the formation of new blood vessels from existing ones and represents a key event in the development and progression of tumors in response to hypoxia. Angiogenic growth factors (AGFs) [i.e. vascular endothelial growth factor (VEGF-A), placental growth factor (PlGF), stromal-derived factor-1 (SDF-1)] and hypoxia have all been implicated in endothelial and tumor cells proliferation, as well as in cancer stem self-renewal and metastasis. AGFs have also been identified as factors responsible for tumor-associated immunosuppression. Indeed, rising evidence has revealed that drugs targeting VEGF/VEGFR signaling can counteract tumor-induced immunosuppression; on the other hand, immune-mediated mechanisms are able to regulate the response to antiangiogenic therapy, making the two processes mutually interconnected. The AGFs-hypoxia axis is a typical feature of the tumor microenvironment associated with inflammation. The AGFs-hypoxia axis has, indeed, the ability to recruit myeloid immune cells, such as tumor-associated macrophages (TAMs) and myeloid-derived suppressor cells (MDSC), into the tumor milieu, creating a diffuse tolerogenic environment that alters the normal hematopoiesis, favoring the expansion of recruited cells and, at the same time, preventing their local differentiation. Moreover, the AGFs-hypoxia axis can also modify the maturation of dendritic cells (DCs), attenuate the Th1 immune response, impair the activity of cytotoxic T lymphocytes and NK cells, and promote T regulatory (Treg) polarization.
Although the AGF-hypoxia axis may be context-dependent, its ability to recruit mostly monocyte-macrophage lineage, such as CD11c+ DC cells, might act as an additional source of VEGF, favoring the development of high endothelial venules (HEV) and ultimately contributing to the generation of tertiary lymphoid structures (TLS). TLS are ectopic lymphoid aggregates occurring in tissues at site of unresolved inflammation and cancer and TLS density has been correlated with prolonged patients' survival in different type of tumors, as they can improve the local and systemic immune response against tumor cells.

While many studies have focused on the impact of the immune system in modulating angiogenesis in the tumor microenvironment (TME), thus allowing for tumor growth and invasiveness, less attention has been paid to the effects of AGFs-hypoxia in regulating the immune response during the tumor promotion and progression. Therefore, there is an urgent need to understand the intricate interplay established in TME between AGFs- hypoxia and the immune cells that blunt the anti-tumor immune response. This Research Topic will focus on the most recent findings concerning the molecular and cellular mechanisms involving AGFs-hypoxia and the immune cells in tumors, in order to identify possible therapeutic targets. We welcome the submission of Reviews, Mini-Reviews, and Original Research articles that can offer new insights into the following sub-topics:

• Cross-talk between angiogenic growth factors-hypoxia and cells of innate immunity in the TME.
• Cross-talk between angiogenic growth factors-hypoxia and cells of adaptive immunity in the TME.
• Reciprocal interplay between different immune cell types (innate or adaptive) in a TME characterized by presence of AGFs and hypoxia
• Endothelial-immune cells interplay during vascular inflammation and metastasis.
• Impact of AGFs-hypoxia in generating TLS.
• Predicting and optimizing cellular responses to therapeutic strategies that target the AGFs-hypoxia axis