Multifaceted Role of the Placental Growth Factor (PlGF) in the Antitumor Immune Response and Cancer Progression

Abstract

The sharing of molecules function that affects both tumor growth and neoangiogenesis with cells of the immune system creates a mutual interplay that impairs the host's immune response against tumor progression. Increasing evidence shows that tumors are able to create an immunosuppressive microenvironment by recruiting specific immune cells. Moreover, molecules produced by tumor and inflammatory cells in the tumor microenvironment create an immunosuppressive milieu able to inhibit the development of an efficient immune response against cancer cells and thus fostering tumor growth and progression. In addition, the immunoediting could select cancer cells that are less immunogenic or more resistant to lysis. In this review, we summarize recent findings regarding the immunomodulatory effects and cancer progression of the angiogenic growth factor namely placental growth factor (PlGF) and address the biological complex effects of this cytokine. Different pathways of the innate and adaptive immune response in which, directly or indirectly, PlGF is involved in promoting tumor immune escape and metastasis will be described. PlGF is important for building up vascular structures and functions. Although PlGF effects on vascular and tumor growth have been widely summarized, its functions in modulating the immune intra-tumoral microenvironment have been less highlighted. In agreement with PlGF functions, different antitumor strategies can be envisioned.

Keywords: PlGF; VEGF; VEGFR; cancer progression.

Figure 1

Pleotropic effects of placental growth factor. PlGF promotes the recruitment of VEGFR1⁺ hematopoietic stem cells (HSC), stimulates the recruitment and/or activation (e.g., cytokines production) of monocytes and activates macrophages, enhances the proliferation and survival of macrophages, blunts the antitumor immune response and stimulates the proliferation of mesenchymal fibroblasts and recruits myeloid progenitors to growing sprouts and collateral vessels. Abbreviations: PI3K, phosphoinositide 3-kinase; ERK, extracellular signal–regulated kinase, PG-E2, prostaglandin E2; PG-F2α, prostaglandin F2α; COX-2, cicloxigenase-2; MHC-II, major histocompatibility complex-II; LPS, lipopolysaccharides; DCs, dendritic cells; IL-2 Rα, IL-2 high affinity receptor; MMP9, matrix metallopeptidase 9; TAMs, tumor associated macrophages; 15-(S)-HETE, 15-Hydroxyeicosatetraenoic acid.

Figure 2

The effects of PlGF on adaptive immune cells. The lack of maturation of dendritic cells in the presence of PlGF prevents the activation of naïve CD4⁺ T cells due to the reduced expression of costimulatory molecules, and results in both the suppression of naïve CD4⁺ T cell proliferation and Th1 polarization. PlGF also stimulates the proliferation of CD4⁺VEGFR1^high T cells and TGF-β+ regulatory B cells (Bregs). PlGF, by the induction of tumor-associated macrophages (TAMs) polarization, can mediate immunosuppression of CD8⁺ tumor infiltrating lymphocytes (TIL). Neuropilin-1 (NRP1) receptor on T cells involved in the immunological synapse between Treg cells and immature DCs (iDCs) induces immunosuppression due to delay iDCs maturation. Abbreviations: APCs, antigen presenting cells; MHC, major histocompatibility complex; NFAT-1, nuclear factor of activated T cells-1; IL-2 Rα, IL-2 high affinity receptor.