Expansion of tumor-associated Treg cells upon disruption of a CTLA-4-dependent feedback loop

Marangoni, Francesco; Zhakyp, Ademi; Corsini, Michela; Geels, Shannon; Carrizosa, Esteban; Thelen, Martin; Mani, V.; Prüßmann, Jasper N.; Warner, Ross D.; Ozga, Aleksandra J.; Pilato, Mauro Di; Othy, Shivashankar; Mempel, Thorsten R.

doi:10.1016/j.cell.2021.05.027

Cited by 108 publications

(112 citation statements)

References 107 publications

(143 reference statements)

Supporting

Mentioning

Contrasting

Unclassified

Order By: Relevance

“…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].…”

Section: Fgfris In A/m Ubc Act As a Dual Modulator Of Tumor Cells And The Tmementioning

confidence: 99%

“…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].…”

Section: Fgfris In A/m Ubc Act As a Dual Modulator Of Tumor Cells And The Tmementioning

confidence: 99%

“…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].…”

Section: Monotherapy Fgfr-targeting Strategies For A/m Ubcmentioning

confidence: 99%

“…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].…”

Section: Mechanisms Underlying Therapeutic Resistance To Fgfri In A/m Ubcmentioning

confidence: 99%

See 3 more Smart Citations

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

Lee

Seo

2021

IJMS

View full text Add to dashboard Cite

Locally advanced or metastatic urothelial bladder cancer (a/m UBC) is currently treated using platinum-based combination chemotherapy. Immune checkpoint inhibitors (ICIs) are the preferred second-line treatment options for cisplatin-eligible a/m UBC patients and as first-line options in cisplatin-ineligible settings. However, the response rates for ICI monotherapy are modest (~20%), which necessitates the exploration of alternative strategies. Dysregulated activation of fibroblast growth factor receptor (FGFR) signaling enhances tumor proliferation, survival, invasion, angiogenesis, and immune evasion. The recent U.S. Food and Drug Administration approval of erdafitinib and the emergence of other potent and selective FGFR inhibitors (FGFRis) have shifted the treatment paradigm for patients with a/m UBC harboring actionable FGFR2 or FGFR3 genomic alterations, who often have a minimal-to-modest response to ICIs. FGFRi–ICI combinations are therefore worth exploring, and their preliminary response rates and safety profiles are promising. In the present review, we summarize the impact of altered FGFR signaling on a/m UBC tumor evolution, the clinical development of FGFRis, the rationale for FGFRi–ICI combinations, current trials, and prospective research directions.

show abstract

Section: Fgfris In A/m Ubc Act As a Dual Modulator Of Tumor Cells And The Tmementioning

confidence: 99%

Section: Fgfris In A/m Ubc Act As a Dual Modulator Of Tumor Cells And The Tmementioning

confidence: 99%

Section: Monotherapy Fgfr-targeting Strategies For A/m Ubcmentioning

confidence: 99%

Section: Mechanisms Underlying Therapeutic Resistance To Fgfri In A/m Ubcmentioning

confidence: 99%

See 2 more Smart Citations

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

Lee

Seo

2021

IJMS

View full text Add to dashboard Cite

show abstract

“…Treg cells belong to a typical class of immunosuppressive cells. In particular, the CD4 + subset of forkhead box P3 (FOXP3) Tregs can play an important role in mediating tumor immune tolerance ( 124 ). It has been shown that the levels of ROS in the microenvironment are associated with immune tolerance mediated by Treg cells ( 125 ).…”

Section: Ros and Tmementioning

confidence: 99%

Role of reactive oxygen species in tumors based on the ‘seed and soil’ theory: A complex interaction (Review)

Liang

et al. 2021

Oncol Rep

View full text Add to dashboard Cite

Tumor microenvironment (TME) can serve as the 'soil' for the growth and survival of tumor cells and function synergically with tumor cells to mediate tumor progression and therapeutic resistance. Reactive oxygen species (ROS) is somewhat of a double-edged sword for tumors. Accumulating evidence has reported that regulating ROS levels can serve an anti-tumor role in the TME, including the promotion of cancer cell apoptosis, inhibition of angiogenesis, preventing immune escape, manipulating tumor metabolic reorganization and improving drug resistance. In the present review, the potential role of ROS in anti-tumor therapy was summarized, including the possibility of directly or indirectly targeting the TME. Contents 1. Introduction 2. ROS and TME 3. ROS and tumor drug resistance 4. Conclusions

show abstract

Nanoengineering Calcium Peroxide‐Based Site‐Specific Delivery Platform to Efficiently Activate the cGAS‐STING Pathway for Cancer Immunotherapy by Amplified Endoplasmic Reticulum Stress

Zhang,

Tian,

Qin

et al. 2024

Adv Funct Materials

View full text Add to dashboard Cite

Currently, the understanding of the cyclic GMP‐AMP synthase (cGAS)‐stimulator of interferon genes (STING) pathway's involvement in efficient immunotherapy mainly revolves around the role of mitochondria or nucleus modulation. Nonetheless, the role of endoplasmic reticulum (ER) stress in activating the cGAS‐STING mechanism to boost immunity against tumors remains essentially unexplored. Herein, novel findings demonstrating that ER stress can be used as a strategy for stimulating the cGAS‐STING pathway, thereby augmenting the immune response against cancer, are presented. To accomplish this objective, ER‐targeting p‐methylbenzene sulfonamide‐tailored IR780 (p‐780) is synthesized and it is loaded into CaO2 nanoparticles, which are further functionalized with distearoyl phosphoethanolamine‐polyethylene glycol（DSPE‐PEG）‐biotin to form PEG/CaO2@p‐780 NPs. The disruption of calcium homeostasis, coupled with the heightened levels of reactive oxygen species (ROS) mediated by p‐780, along with hyperpyrexia, collectively contributes to the amplification of endoplasmic reticulum (ER) stress. This cascade of events effectively triggers the cGAS‐STING pathway and, in parallel, facilitates the degradation of the programmed cell death 1 ligand 1 (PD‐L1) protein. In addition, oxygen released through CaO2 decomposition is expected to promote p‐780–mediated phototherapy, while reversing the immunosuppressive tumor microenvironment associated with hypoxia. Furthermore, DSPE‐PEG‐biotin facilitates tumor site‐specific drug delivery through active targeting mediated by the biotin receptor. Collectively, PEG/CaO2@p‐780 nanoparticles successfully activate systemic antitumor immunity by enhancing ER stress.

show abstract

Expansion of tumor-associated Treg cells upon disruption of a CTLA-4-dependent feedback loop

Cited by 108 publications

References 107 publications

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

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

Role of reactive oxygen species in tumors based on the ‘seed and soil’ theory: A complex interaction (Review)

Nanoengineering Calcium Peroxide‐Based Site‐Specific Delivery Platform to Efficiently Activate the cGAS‐STING Pathway for Cancer Immunotherapy by Amplified Endoplasmic Reticulum Stress

Contact Info

Product

Resources

About