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Review
. 2022 May 29;18(9):3845-3858.
doi: 10.7150/ijbs.70958. eCollection 2022.

VEGF/VEGFR-Targeted Therapy and Immunotherapy in Non-small Cell Lung Cancer: Targeting the Tumor Microenvironment

Yueshui Zhao  1   2   3 , Sipeng Guo  1   2 , Jian Deng  1   2 , Jing Shen  1   2   3 , Fukuan Du  1   2   3 , Xu Wu  1   2   3 , Yu Chen  1   2   3 , Mingxing Li  1   2   3 , Meijuan Chen  1   4 , Xiaobing Li  1   2 , Wanping Li  1   2 , Li Gu  1   2 , Yuhong Sun  1   2 , Qinglian Wen  4   2   3 , Jing Li  5   6 , Zhangang Xiao  4   2   3
Affiliations
Review

VEGF/VEGFR-Targeted Therapy and Immunotherapy in Non-small Cell Lung Cancer: Targeting the Tumor Microenvironment

Yueshui Zhao et al. Int J Biol Sci. .

Abstract

Non-small cell lung cancer (NSCLC) is the leading cause of death by cancer worldwide. Despite developments in therapeutic approaches for the past few decades, the 5-year survival rate of patients with NSCLC remains low. NSCLC tumor is a complex, heterogeneous microenvironment, comprising blood vessels, cancer cells, immune cells, and stroma cells. Vascular endothelial growth factors (VEGFs) are a major mediator to induce tumor microvasculature and are associated with the progression, recurrence, and metastasis of NSCLC. Current treatment medicines targeting VEGF/VEGF receptor (VEGFR) pathway, including neutralizing antibodies to VEGF or VEGFR and receptor tyrosine kinase inhibitors, have shown good treatment efficacy in patients with NSCLC. VEGF is not only an important angiogenic factor but also an immunomodulator of tumor microenvironment (TME). VEGFs can suppress antigen presentation, stimulate activity of regulatory T (Treg) cells, and tumor-associated macrophages, which in turn promote an immune suppressive microenvironment in NSCLC. The present review focuses on the angiogenic and non-angiogenic functions of VEGF in NSCLC, especially the interaction between VEGF and the cellular components of the TME. Additionally, we discuss recent preclinical and clinical studies to explore VEGF/VEGFR-targeted compounds and immunotherapy as novel approaches targeting the TME for the treatment of NSCLC.

Keywords: NSCLC; VEGF/VEGFR pathway; clinical trials; immunotherapy; tumor microenvironment.

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Conflict of interest statement

Competing Interests: The authors have declared that no competing interest exists.

Figures

Figure 1
Figure 1
The VEGF-VEGFR signaling pathway. VEGF-A binds to VEGFR-2 for dimerization, autophosphorylation, and activation leading to endothelial cell survival, proliferation, permeability, and migration. mTOR, mammalian target of rapamycin; MAPK, mitogen-activated protein kinase; MEK, MAP kinase kinase.
Figure 2
Figure 2
The effect of VEGF on CTL, Treg, and TAM. A) VEGF-A enhances the expression of PD-1 and FasL on CTL, thereby promoting CTL cell failure and leading to immunosuppression. B) VEGF-A can make Treg recruited in the tumor microenvironment and increase the number of Treg. VEGF-A can induce Treg differentiation by producing immature DC. Treg cells inhibit the activation of target cells through FoxP3+ direct contact; up-regulate the expression of CTLA-4; inhibit the expression of IL-2, LAG-3, CD39/73, and NRP-1; or cause immunosuppression by producing soluble immunosuppressive molecules. C) Under the action of VEGF-A, monocytes/macrophages in the blood are gathered around tumor cells and differentiate into TAM. The M2 cells in TAM can promote tumorigenesis and development.
Figure 3
Figure 3
The effect of VEGF on DC, MDSC, and NK cell. A) VEGF-A can bind to VEGFR1 on CD34+ HPC, inhibit NF-κB, an activator of transcription factors in these cells, and inhibit the differentiation and maturation of DC. VEGF-A can also increase the expression of PD-1 in DC, resulting in a decrease in the number of DCs. To inhibit the activation of T cells by mature DCs. Lead to immunosuppression. B) VEGF-A can promote the expansion of MDSC, and MDSC can inhibit the proliferation of tumor-specific T cells and promote the development of Treg. C) VEGF-A can inhibit the differentiation of NK cells by inhibiting DC maturation. VEGF can also increase the number of MDSCs and inhibit the function of NK cells.
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