A CCR4 antagonist reverses the tumor-promoting microenvironment of renal cancer

Berlato, Chiara; Khan, Moddasar N.; Schioppa, Tiziana; Thompson, Richard G.; Maniati, Eleni; Montfort, Anne; Jangani, Maryam; Canosa, Monica; Kulbe, Hagen; Hagemann, Urs B.; Duncan, Alexander; Fletcher, Laura; Wilkinson, Robert W.; Powles, Thomas; Quezada, Sergio A.; Balkwill, Frances R.

doi:10.1172/jci82976

Cited by 84 publications

(67 citation statements)

References 26 publications

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“…Th2‐like Tregs, distinguished by the expression of the chemokine receptor CCR4, are increased in patients with melanoma and colorectal cancer, and exhibit a heightened capacity to suppress effector T‐cells . Antibodies against CCR4 can reduce the number of TI‐Tregs in murine tumours, and a humanized anti‐CCR4 antibody, KW‐0761, is being tested in early clinical trials in patients . Interestingly, treating T‐cells with CCL17 (a CCR4 interacting chemokine) can directly inhibit the production of the Th1 cytokine IFN‐ γ , thus implicating chemokines themselves as factors that can directly reprogramme the functionality of T‐cells .…”

Section: Activation and Differentiation Of Ti‐tregsmentioning

confidence: 99%

“…Antibodies against CCR4 can reduce the number of TI‐Tregs in murine tumours, and a humanized anti‐CCR4 antibody, KW‐0761, is being tested in early clinical trials in patients . Interestingly, treating T‐cells with CCL17 (a CCR4 interacting chemokine) can directly inhibit the production of the Th1 cytokine IFN‐ γ , thus implicating chemokines themselves as factors that can directly reprogramme the functionality of T‐cells . CCR8, another chemokine receptor associated with Th2 cells, may prove to be a superior target, as it was found highly expressed on TI‐Tregs in multiple solid tumours, but in a more restricted fashion than CCR4 .…”

Section: Activation and Differentiation Of Ti‐tregsmentioning

confidence: 99%

“…41 Interestingly, treating T-cells with CCL17 (a CCR4 interacting chemokine) can directly inhibit the production of the Th1 cytokine IFN-c, thus implicating chemokines themselves as factors that can directly reprogramme the functionality of T-cells. 40 CCR8, another chemokine receptor associated with Th2 cells, may prove to be a superior target, as it was found highly expressed on TI-Tregs in multiple solid tumours, but in a more restricted fashion than CCR4. 9,10 However, the type of TI-Tregs may vary in different cancers and patients, as Th1-like Tregs, defined by the expression of T-bet, made up 40% of Foxp3 + cells in a murine model of lung carcinoma, and between 2% and 10% of Tregs from human nonsmall cell lung carcinomas.…”

Section: Chemokine Receptorsmentioning

confidence: 99%

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Treg programming and therapeutic reprogramming in cancer

Ayala

DuPage

2019

Immunology

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Summary Overcoming the immunosuppressive tumour microenvironment is the major challenge impeding cancer immunotherapy today. Regulatory T‐cells (Tregs) are prevalent in nearly all cancers and, as immunosuppressive regulators of immune responses, they are the principal opponents of cancer immunotherapy. However, disabling Tregs systemically causes severe autoimmune toxicity, hastening the need for more selective methods to target intratumoural Tregs. In this review, we discuss a burgeoning new modality to specifically target tumour‐infiltrating Tregs (TI‐Tregs) by reprogramming their functionality from immunosuppressive to immune stimulatory within tumours. As the basis for therapeutic selectivity of TI‐Tregs, we will focus on the defining features of Tregs within cancer: their highly activated state controlled by the engagement of key surface receptors, their distinct metabolic programme, and their unique transcriptional programme. By identifying proteins and pathways that distinguish TI‐Tregs from other Tregs in the body, as well as from the beneficial antitumour effector T‐cells within tumours, we highlight mechanisms to selectively reprogramme TI‐Tregs for the treatment of cancer.

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Section: Activation and Differentiation Of Ti‐tregsmentioning

confidence: 99%

Section: Activation and Differentiation Of Ti‐tregsmentioning

confidence: 99%

Section: Chemokine Receptorsmentioning

confidence: 99%

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Treg programming and therapeutic reprogramming in cancer

Ayala

DuPage

2019

Immunology

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“…Recently, immune checkpoint inhibitors have shown efficacy in the treatment of various solid tumors, including those causing advanced urological cancers . They can stimulate, enhance, and modulate the immune system to recognize and destroy cancer cells .…”

Section: Introductionmentioning

confidence: 99%

“…Recently, immune checkpoint inhibitors have shown efficacy in the treatment of various solid tumors, including those causing advanced urological cancers. [8][9][10] They can stimulate, enhance, and modulate the immune system to recognize and destroy cancer cells. 11 The first clinical successes with immune checkpoint inhibition were reported in melanoma with a cytotoxic T-lymphocyte antigen-4 (CTLA-4) pathway inhibitor, a humanized IgG1 monoclonal antibody for CTLA-4, ipilimumab, demonstrating dramatic and often durable responses.…”

Section: Introductionmentioning

confidence: 99%

Increased infiltration of CCR4‐positive regulatory T cells in prostate cancer tissue is associated with a poor prognosis

et al. 2019

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Background Regulatory T cells (Tregs) play important roles in the suppression of immune responses, including antitumor immune responses. C‐C chemokine receptor 4 (CCR4) is highly expressed on effector Tregs, and anti‐CCR4 antibody is attracting attention as a novel immunotherapeutic agent for solid tumors. This study aimed to evaluate the expression of CCR4‐positive Tregs (CCR4+Tregs) in prostate cancer and estimate the clinical potential of CCR4‐targeting therapy for prostate cancer. Methods A total of 15 radical prostatectomy (RP) specimens and 60 biopsy specimens from individuals diagnosed with prostate cancer were analyzed to evaluate the infiltration of CCR4+Tregs in prostate cancer. The relationships between the number of CCR4+Tregs and clinical parameters were investigated in RP and biopsy specimens. Moreover, the total number of Tregs, CCR4+Tregs, and T cells and the ratio of CCR4+Tregs to Tregs and T cells in biopsy specimens were compared between patients with poor prognosis who progressed to castration‐resistant prostate cancer (CRPC) within 12 months (n = 13) and those with good prognosis who were stable with hormone‐sensitive prostate cancer over 12 months (n = 47). Furthermore, biopsy specimens were divided into two groups: low and high CCR4+Treg expression groups and the prognosis was compared between them. Results There was a higher expression of CCR4+Tregs in RP specimens with a higher (≥8) Gleason score than in those with a lower (<8) Gleason score (P = .041). In biopsy specimens, 65.9% Tregs were positive for CCR4. The number of CCR4+Tregs positively correlated with clinical stage (P < .001) and Gleason score (P = .006). The total number of Tregs and CCR4+Tregs significantly increased in the poor prognosis group compared with that in the good prognosis group (P = .024 and .01, respectively). Furthermore, patients with lower CCR4+Treg expression levels showed a significantly longer time to progression to CRPC (not reached vs 27.3 months; P < .001) and median survival time (not reached vs 69.0 months; P = .014) than those with higher expression levels. Conclusions CCR4+Tregs are highly infiltrated in the prostate tissue of patients with poor prognosis with potential to progress to CRPC. Furthermore, the degree of infiltration of CCR4+Tregs is related to the prognosis of prostate cancer.

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Immunostimulatory effects of Toll‐like receptor ligands as adjuvants in establishing a novel mouse model for pemphigus vulgaris

Gao,

Liu,

Xin

et al. 2024

Clinical & Translational Med

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BackgroundThe meticulous selection of appropriate vaccine adjuvants is crucial for optimizing immune responses. Traditionally, pemphigus vulgaris (PV), an autoimmune disorder, has been modelled using complete Freund's adjuvant (CFA). In this study, we aimed to discern potential variations in immune responses elicited by Toll‐like receptor (TLR) ligands as compared to CFA.MethodsA comprehensive investigation was conducted, comparing the effects of these adjuvants in conjunction with ovalbumin or desmoglein‐3. Flow cytometry was employed to analyse distinct cell subsets, while enzyme‐linked immunosorbent assay quantified antigen‐specific antibodies and cytokine levels. Histological examination of harvested skin tissues and transcriptome analysis of skin lesions were performed to identify differentially expressed genes.ResultsTLR ligands demonstrated efficacy in inducing PV‐like symptoms in wild‐type mice, in contrast to CFA. This underscored the substantial impact of the adjuvant on self‐antigen tolerance. Furthermore, we proposed an enhanced method for establishing a PV model through adoptive transfer, substituting CFA with TLR ligands. Our results revealed that in contrast to the perception that CFA being the most potent immunopotentiator reported, CFA promoted regulatory T cells (Treg), follicular regulatory T cells and IL‐10‐producing neutrophils, whereas TLR ligands downregulated CCL17 and IL‐10. This suggested potential implications for the recruitment and activation of Treg subsets. While B cell and CD8+ T cell responses exhibited similarity, CFA induced less activation in dendritic cell subsets. A novel mouse model of PV and systemic comparison of immunostimulatory effects of adjuvants were provided by this study.ConclusionsThe systematic comparison of CFA and TLR ligands shed light on the distinctive properties of these adjuvants, presenting innovative mouse models for the investigation of pemphigus. This study significantly contributes to adjuvant research and advances our understanding of PV pathogenesis.Key points/highlights Immunization with desmoglein 3 and Toll‐like receptor (TLR) ligands effectively induces pemphigus symptoms in wild‐type mice, whereas complete Freund's adjuvant (CFA) fails. TLR ligands heightened the autoreactivity of donor cells in the adoptive transfer pemphigus model. CFA promoted regulatory T cells and IL‐10‐producing neutrophils, whereas TLR ligands downregulated CCL17 and IL‐10, leading to more effective immune responses.

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A CCR4 antagonist reverses the tumor-promoting microenvironment of renal cancer

Cited by 84 publications

References 26 publications

Treg programming and therapeutic reprogramming in cancer

Treg programming and therapeutic reprogramming in cancer

Increased infiltration of CCR4‐positive regulatory T cells in prostate cancer tissue is associated with a poor prognosis

Immunostimulatory effects of Toll‐like receptor ligands as adjuvants in establishing a novel mouse model for pemphigus vulgaris

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