The Combination of Immune Checkpoint Blockade and Angiogenesis Inhibitors in the Treatment of Advanced Non-Small Cell Lung Cancer

Abstract

Immune checkpoint blockade (ICB) has become a standard treatment for non-small cell lung cancer (NSCLC). However, most patients with NSCLC do not benefit from these treatments. Abnormal vasculature is a hallmark of solid tumors and is involved in tumor immune escape. These abnormalities stem from the increase in the expression of pro-angiogenic factors, which is involved in the regulation of the function and migration of immune cells. Anti-angiogenic agents can normalize blood vessels, and thus transforming the tumor microenvironment from immunosuppressive to immune-supportive by increasing the infiltration and activation of immune cells. Therefore, the combination of immunotherapy with anti-angiogenesis is a promising strategy for cancer treatment. Here, we outline the current understanding of the mechanisms of vascular endothelial growth factor/vascular endothelial growth factor receptor (VEGF/VEGFR) signaling in tumor immune escape and progression, and summarize the preclinical studies and current clinical data of the combination of ICB and anti-angiogenic drugs in the treatment of advanced NSCLC.

Fibroblast Growth Factor Inhibitors for Treating Locally Advanced/Metastatic Bladder Urothelial Carcinomas via Dual Targeting of Tumor-Specific Oncogenic Signaling and the Tumor Immune Microenvironment

“…FGFRis reduce phosphorylation of FGFRs directly and indirectly via their targets, FRS2 and PLC-γ, and inactivate downstream signaling via RAS-ERK, PI3K-AKT, IP3-Ca2+, and DAG-PKC signaling cascades [4,5,8,17,[23][24][25][26]30,[38][39][40][41][42]. In the TME of a/m UBC, the luminal-papillary subtype of the consensus classification is characterized by a high rate of FGFR3 mutations and translocations, suggesting that these tumors may respond to FGFRi [4,5,8,15,17,18,37].…”

“…Moreover, the FGFR3 pathway is activated in non-T-cell-inflamed tumors, which are likely to be intrinsically resistant to ICIs. FGFRi elicits antitumor effects directly in cancer cells by suppressing tumor cell survival, epithelialmesenchymal transition (EMT), invasion, metastasis, and the development of treatment resistance, as well as indirectly through the normalization of the TME, especially paracrine signaling, angiogenesis, and immune evasion (Figure 2) [4,5,8,11,15,17,18,[23][24][25][26]30,[37][38][39][40][41][42][43][44][45].…”

“…As the role of FGF-FGFR signaling in a/m UBC has become clearer, a large number of potential and promising drugs targeting this signaling pathway have been developed. According to their mode of action, they can be divided into three categories: (a) smallmolecule FGFR TKIs (non-selective and selective), (b) anti-FGFR antibodies, and (c) FGF ligand traps and DNA/RNA aptamers [4,5,8,11,15,17,[23][24][25][26]30,[37][38][39][40][41][42][43][44][45] (Figure 2, Table 1). As the FGFR TKIs may target other growth factor receptors because the binding pocket of ATP-competitive FGFRs shares a high degree of homology with other oncogenic RTKs, such as VEGFR and platelet-derived growth factor receptor (PDGFR), these TKIs can be divided into multi-kinase (non-selective) FGFRis and FGFR-specific TKIs (selective) [23][24][25][26]30,43].…”

“…Primary resistance describes an initial lack of treatment response, while secondary resistance describes disease progression after an initial response to treatment and has emerged as a limiting factor in the long-term efficacy of FGFRis [24,50]. A recent review summarized various mechanisms of resistance to FGFRis, including activation of bypass signaling involving amplification or mutations in proteins appertaining to MAPK, PI3K/AKT, EGFR, PLC-γ, and STAT signaling, gatekeeper mutations conferring resistance by interfering with the binding between the receptor and the targeted agents, and intratumor heterogeneity (ITH) [23][24][25][26]30,[38][39][40][41]44,50,63,64]. For example, UBC cells harboring FGFR3-TACC3 fusions acquire resistance to FGFRis through the upregulation of EGFR/HER3-dependent PI3K-AKT signaling [24,50], and mutations occurring at gatekeeper residues in FGFR, such as FGFR1 V561M and FGFR2 V565I, lead to steric hindrance within the ATP-binding pocket, which precludes the entry and binding of multiple FGFRis [24,50,63,65].…”

“…A major mechanism of immune escape of cancer cells is the exhaustion of CD8+ T cells, which recognize tumor antigens [23][24][25][26]30,[38][39][40][41]44]. ICIs work to restore antitumor T-cell functions [4,5,7,8,24,43]; however, the lack of existing immune cells in the TME leads to an inadequate response to monotherapy with ICIs [4,5,7,8,24,43].…”