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

Watanabe, Masaru; Kanao, Kent; Suzuki, Susumu; Muramatsu, Hiroyuki; Morinaga, Singo; Kajikawa, Keishi; Kobayashi, Ichiro; Nishikawa, Genya; Kato, Yoshiharu; Zennami, Kenji; Nakamura, Kogenta; Tsuzuki, Toyonori; Yoshikawa, Kazuhiro; Ueda, Ryuzo; Sumitomo, Makoto

doi:10.1002/pros.23890

Cited by 51 publications

(42 citation statements)

References 37 publications

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“…Interestingly, in this study, a response was observed in prostate cancer, which is considered an immunologically "cold" tumor. While CCR4 þ Tregs have been shown to be associated with poor prognosis in prostate cancer (43), there is evidence of response of prostate cancer to singleagent CTLA-4 blockade (44,45). Thus, it is unclear whether our responding patient could have benefitted from tremelimumab alone, or whether addition of mogamulizumab was beneficial.…”

Section: Discussionmentioning

confidence: 95%

Mogamulizumab in Combination with Durvalumab or Tremelimumab in Patients with Advanced Solid Tumors: A Phase I Study

Zamarin

Hamid

Nayak-Kapoor

et al. 2020

Clinical Cancer Research

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The study goal was to determine safety, antitumor activity, and pharmacodynamic profile of mogamulizumab, an anti-CC chemokine receptor 4 (anti-CCR4) mAb targeting effector regulatory T cells (eTreg), in combination with mAb checkpoint inhibitors durvalumab or tremelimumab. Patients and Methods: This was a multicenter, phase I, dose escalation study, followed by disease-specific cohort expansion (NCT02301130). Mogamulizumab dose escalation proceeded with concurrent dose escalation of durvalumab or tremelimumab in patients with advanced solid tumors. Cohort expansion occurred with mogamulizumab 1 mg/kg plus durvalumab 10 mg/kg or tremelimumab 10 mg/kg in patients with advanced pancreatic cancer. Results: Forty patients were enrolled during dose escalation, followed by 24 patients during dose expansion. No dose-limiting toxicities occurred during dose escalation. No new or unexpected toxicities were seen. Tolerability, the primary endpoint, was acceptable utilizing mogamulizumab 1 mg/kg plus durvalumab or tremelimumab 10 mg/kg in the combined dose escalation and dose expansion cohorts (each n ¼ 19). At these doses, the objective response rate was 5.3% (95% confidence interval, 0.1%-26.0%; one partial response) with each combination treatment. At all doses, mogamulizumab treatment led to almost complete depletion of peripheral eTregs, as well as reduction of intratumoral Tregs in the majority of patients. There was no clear correlation of clinical response with peripheral or intratumoral reduction in CCR4 þ eTregs or with baseline degree of CCR4 þ expression.

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Section: Discussionmentioning

confidence: 95%

Mogamulizumab in Combination with Durvalumab or Tremelimumab in Patients with Advanced Solid Tumors: A Phase I Study

Zamarin

Hamid

Nayak-Kapoor

et al. 2020

Clinical Cancer Research

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“…Similarly, because of a significant pro-cancer effect, it is postulated that treatment may target the functioning of CCL3/MIP-1α [19,255], CCL5/RANTES [45,256]. Another therapeutic approach is the use of anti-CCR4 antibodies or CCR4 antagonists ( receptor for CCL17/TARC and CCL22/MDC) in cancer therapy [257][258][259] to reduce the accumulation of T reg and thus enhance the immunotherapy and anticancer response of the immune system. Some researchers also postulate targeting the CCL20/LARC→CCR6 axis [260,261], which causes chemoresistance and migration of neoplastic cells, and so any disorder in the function of CCL20/LARC should increase the activity of anticancer drugs.…”

Section: β Chemokines As a Therapeutic Target In Cancer Therapymentioning

confidence: 99%

Section: Hypoxic Microenvironment As a Therapeutic Targetmentioning

confidence: 99%

Hypoxia Alters the Expression of CC Chemokines and CC Chemokine Receptors in a Tumor–A Literature Review

Korbecki

Kojder

Barczak

et al. 2020

IJMS

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Hypoxia, i.e., oxygen deficiency condition, is one of the most important factors promoting the growth of tumors. Since its effect on the chemokine system is crucial in understanding the changes in the recruitment of cells to a tumor niche, in this review we have gathered all the available data about the impact of hypoxia on β chemokines. In the introduction, we present the chronic (continuous, non-interrupted) and cycling (intermittent, transient) hypoxia together with the mechanisms of activation of hypoxia inducible factors (HIF-1 and HIF-2) and NF-κB. Then we describe the effect of hypoxia on the expression of chemokines with the CC motif: CCL1, CCL2, CCL3, CCL4, CCL5, CCL7, CCL8, CCL11, CCL13, CCL15, CCL16, CCL17, CCL18, CCL19, CCL20, CCL21, CCL22, CCL24, CCL25, CCL26, CCL27, CCL28 together with CC chemokine receptors: CCR1, CCR2, CCR3, CCR4, CCR5, CCR6, CCR7, CCR8, CCR9, and CCR10. To better understand the effect of hypoxia on neoplastic processes and changes in the expression of the described proteins, we summarize the available data in a table which shows the effect of individual chemokines on angiogenesis, lymphangiogenesis, and recruitment of eosinophils, myeloid-derived suppressor cells (MDSC), regulatory T cells (Treg), and tumor-associated macrophages (TAM) to a tumor niche.

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“…Recently, studies showed that CCR4 is highly expressed on circulating Tregs [21]. Tregs is recruited at tumor sites in many cancers, such as breast cancer [22] and colorectal cancer [23].…”

Section: Discussionmentioning

confidence: 99%

MiRNA-6089 inhibits rheumatoid arthritis fibroblast-like synoviocytes proliferation and induces apoptosis by targeting CCR4

Lin

Wang

Zhang

et al. 2020

Archives of Physiology and Biochemistry

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Background: Growing data have indicated that broblast-like synoviocytes (FLS) and miRNAs are implicated in the pathogenesis of rheumatoid arthritis (RA). This study was aimed to evaluate the function of miR-6089 in the regulation of RA-FLSs. Methods: The expression of miR-6089 was measured by quantitative real time PCR (qRT-PCR). The RA-FLSs were transfected with si-CCR4 plasmids or miR-6089 mimic, and subjected to CCK-8 and ow cytometry to analyze proliferation and apoptosis. The concentrations of MMP-1, TNF-α and IL-6 in RA-FLSs supernatant were detected using ELISA. The protein expression of caspase-3,-8 and-9 was detected using western blot. Results: The levels of miR-6089 were detected to be signi cantly lower in the synovial tissues and FLSs of RA than in the synovial tissues and FLSs of healthy controls. The miR-6089 up-regulation in RA-FLSs signi cantly inhibited the proliferation and promoted cell apoptosis accompany with an increase protein expression of caspase-3,-8 and-9. Furthermore, CCR4 was determined to directly target miR-6089, and its expression was signi cantly increased in the synovial tissues of RA than in the synovial tissues of healthy controls. Moreover, CCR4 overexpression effectively reversed the effect on proliferation and apoptosis induced by miR-6089 in RA-FLSs. Conclusion: Our results revealed that miR-6089 may be a potential target for RA prevention and therapy of RA.

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

Cited by 51 publications

References 37 publications

Mogamulizumab in Combination with Durvalumab or Tremelimumab in Patients with Advanced Solid Tumors: A Phase I Study

Mogamulizumab in Combination with Durvalumab or Tremelimumab in Patients with Advanced Solid Tumors: A Phase I Study

Hypoxia Alters the Expression of CC Chemokines and CC Chemokine Receptors in a Tumor–A Literature Review

MiRNA-6089 inhibits rheumatoid arthritis fibroblast-like synoviocytes proliferation and induces apoptosis by targeting CCR4

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