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

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.

Upregulation of HMGB1 in tumor-associated macrophages induced by tumor cell-derived lactate further promotes colorectal cancer progression

“…Studies showed that lactic acid produced by the enhanced glycolytic activity of cancer cells caused TME acidification. The acidified TME induced regulatory macrophages through G protein–coupled receptors and IL-1β-converting enzymes, enabling the production of VEGF and arginase [ 36 ]. The increased expression by TAMs induced the M2 phenotype of TAMs [ 37 ].…”

RBM17 expression is associated with the efficacy of immune checkpoint inhibitor monotherapy in non-small cell lung cancer with low PD-L1 expression

“…In NSCLC, VEGFR2 expression stimulates VEGF production in tumor cells 18 . VEGF not only promotes tumor angiogenesis 19 , but also directly and indirectly affects the tumor immune environment [20][21][22][23][24] , which has been implicated in ICI resistance 25 . These ndings might explain the better e cacy of ICI monotherapy in RBM17-positive patients as a result of the low expression level of VEGFR2.…”

Advanced polymer hydrogels that promote diabetic ulcer healing: mechanisms, classifications, and medical applications

“…VEGF, for example, is a highly specific pro-vascular endothelial GF with the highest activity and specificity among known angiogenic factors. Studies have shown that VEGF binds to VEGFR on the endothelial cell membrane, causing autophosphorylation of the receptor, which in turn leads to the conversion of the inactive Ras-GDP complex to the active Ras-GTP complex, thereby activating MAPK, inducing endothelial cell proliferation and accelerating neovascularization [ 257 , 258 ].…”