Immunotherapy in the Treatment of Urothelial Bladder Cancer: Insights From Single-Cell Analysis

Abstract

Urothelial bladder cancer (UBC) is a global challenge of public health with limited therapeutic options. Although the emergence of cancer immunotherapy, most notably immune checkpoint inhibitors, represents a major breakthrough in the past decade, many patients still suffer from unsatisfactory clinical outcome. A thorough understanding of the fundamental cellular and molecular mechanisms responsible for antitumor immunity may lead to optimized treatment guidelines and new immunotherapeutic strategies. With technological developments and protocol refinements, single-cell approaches have become powerful tools that provide unprecedented insights into the kaleidoscopic tumor microenvironment and intricate cell-cell communications. In this review, we summarize recent applications of single-cell analysis in characterizing the UBC multicellular ecosystem, and discuss how to leverage the high-resolution information for more effective immune-based therapies.

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].…”