The Intricate Innate Immune-Cancer Cell Relationship in the Context of Tumor Angiogenesis, Immunity and Microbiota: the Angiogenic Switch in the Tumor Microenvironment as a Key Target for Immunotherapies

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Background

The tumor microenvironment represents a complex multicellular complex network which comprises host-derived stromal, immune and endothelial cells with potential dual and paradoxical role in tumor development and dissemination. In addition, the metabolic tumor microenvironment (i.e. hypoxia) is a key determinant in shaping stroma reactivity and angiogenesis regulation. The critical role of angiogenesis in promoting tumor growth and metastasis is strongly established. However, tumors show considerable variation in angiogenic characteristics and in their sensitivity to antiangiogenic therapy. Tumor angiogenesis involves many types of inflammatory and suppressive cells such as tumor-associated macrophages, mast cells, myeloid-derived suppressor cells, but also proangiogenic NK cells and subsets of innate immune cells. Endothelial cells line all blood vessels, and change the behavior in response to their microenvironment. Secreted cytokines such as Vascular endothelial growth factor (VEGF), fibroblast growth factor (FGF), placental growth factor (PlGF) are not only major proangiogenic factors but are also immune modulators, which increase angiogenesis and lead to immune suppression. In this context, a role for the microbiota has also emerged in the regulation of tumor growth and neovasculature. Taken together, the tumor microenvironment is not simply pro-angiogenic or pro/anti-inflammatory, rather is a dynamic milieu of complex interactions and cellular consequences.

Indeed, innate immune cells have the ability to recognize and orchestrate an antitumor response leading to cancer cell death, however in the meantime they can become pro-tumorigenic and help various critical steps of tumor growth, such as tumor progression, invasiveness, dissemination and clinical outcome. Also, the microbiota can play an important role in different types of cancers, regulating tumor angiogenesis, metastasis and efficacy of therapies.
For cell growth, progression and dissemination, tumor cells must interact with innate immune cells in order to regulate a complex modified tissue compartment. In the tumor microenvironment, there are different key processes that must be established to ensure tumor growth, such as triggering a tumor promoting inflammation, inducing an antigenic immune evasion, activating an angiogenesis switch, and driving metastatic competence. All these factors, points out the key role of the immune system in neoplastic disease.
The fine knowledge of all the actors supporting vascular networks of growing tumors, as well as inhibitory signaling pathways represent the challenge of the new therapies, in particular combined approaches using immune checkpoint inhibitors and antiangiogenic therapies.
Growing data have highlighted a key role of various microbiota in the inflammatory response and in the angiogenic process in several associated human diseases including cancer.
The aim of this Research Topic is to provide a broad overview on the topic of Innate immune-Cancer cell crosstalk together with the microbiota regulating tumor angiogenesis, progression and metastasis” in the context of human cancers, preclinical cancer models, drug resistance, and immunotherapies.

To this end, we welcome experts in this field to contribute with Original Research, Mini-Review, Review, and Perspective articles. Contributions are not limited to the fields that are mentioned in the keywords.

Keywords: Cancer, Tumor microenvironment, Inflammatory cells, Angiogenesis, Microbiota, Microbiome, Metastasis, Immunotherapies

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