Effector/Memory but Not Naive Regulatory T Cells Are Responsible for the Loss of Concomitant Tumor Immunity

Lin, Yung‐Chang; Chang, Li-Yuan; Huang, Ching-Tai; Peng, Huimin; Dutta, Alo; Chen, Tse–Ching; Yeh, Chau‐Ting; Lin, Chun‐Yen

doi:10.4049/jimmunol.0803829

Cited by 44 publications

(54 citation statements)

References 48 publications

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“…These CD103 + Tregs are more potent in suppressing harmful inflammatory reactions compared with CD103 2 Tregs in different mouse models of autoimmune diseases and Leishmania infection (3,4,6). In contrast, we also reported that CD103 + Tregs were potent suppressors of anti-tumor immune responses in tumor-bearing mice (8). Recent studies have also shown that CD103 is a hallmark of tumor-infiltrating Tregs in TGF-bsecreting tumor (9).…”

Section: R Egulatory T Cells (Tregs) Play An Important Role In the Mamentioning

confidence: 63%

“…It has been shown that chemokine receptors CCR3, CCR4, and CCR5 could mediate trafficking of Tregs to tumors (8,(14)(15)(16). We next examined the expression of these chemokine receptors on CD103 + Tregs in the spleen and tumors of mice bearing CT26 tumors.…”

Section: Tregs In Vitromentioning

confidence: 99%

“…All Abs were purchased from BD Biosciences or eBioscience, except for anti-CCR3 mAb (R&D Systems) and anti-CCR4 mAb (BioLegend). Single-cell suspensions were stained for surface or intracellular proteins as previously described (8,14).…”

Section: Flow Cytometrymentioning

confidence: 99%

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The Indispensable Role of CCR5 for In Vivo Suppressor Function of Tumor-Derived CD103+ Effector/Memory Regulatory T Cells

Chang

Lin

Kang

et al. 2012

The Journal of Immunology

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CD103 is a marker for identification of effector/memory regulatory T cells (Tregs). CD103+ Tregs are potent suppressors of tissue inflammation in several infectious diseases, autoimmune diseases, and cancers. However, the underlying mechanisms for this potent suppression ability remain unclear. The current study was designed to clarify this issue. Unexpectedly, we found both CD103+ and CD103− Tregs had similar suppression capacity in vitro. We then chose a murine tumor model for investigation of the in vivo behavior of these Tregs. The suppression ability in vivo against the anti-tumor ability of CD8+ T cells was restricted to CD103+ Tregs although both Tregs had equal in vitro suppression ability. In addition, CD103+ Tregs expressed significantly higher levels of CCR5 than those of CD103− Tregs and accumulated more in tumors than did CD103− Tregs. Furthermore, blockade of CCR5 signaling, either by CCR5−/−CD103+ Tregs or by CCL5 knockdown tumor, could reduce the migration of CD103+ Tregs into tumors and impair their in vivo suppression ability. In conclusion, these results indicate that the potent in vivo suppression ability of CD103+ Tregs is due to the tissue-migration ability through CCR5 expression.

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Section: R Egulatory T Cells (Tregs) Play An Important Role In the Mamentioning

confidence: 63%

Section: Tregs In Vitromentioning

confidence: 99%

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The Indispensable Role of CCR5 for In Vivo Suppressor Function of Tumor-Derived CD103+ Effector/Memory Regulatory T Cells

Chang

Lin

Kang

et al. 2012

The Journal of Immunology

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“…4,5 In human studies, Sakaguchi's group demonstrated CD45RA ¡ Foxp3 high Treg cells as effector Treg cells which are increased in patients with cancer. 1,6 We have also shown these CD45RA ¡ Foxp3 high effector Treg cells were highly suppressive, accumulated in tumor tissues and correlated with disease progression in patients with CRC.…”

Section: Introductionmentioning

confidence: 99%

“…This effect is lost during tumor progression as shown in our previous studies. 4 We investigated whether this loss of concomitant tumor immunity is tumor specific or not. We chose CT26 cells and BNL cells for these studies.…”

Section: Introductionmentioning

confidence: 99%

Blockade of TNF-α signaling benefits cancer therapy by suppressing effector regulatory T cell expansion

et al. 2015

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Effector but not naive regulatory T cells (Treg cells) can accumulate in the peripheral blood as well as the tumor microenvironment, expand during tumor progression and be one of the main suppressors for antitumor immunity. However, the underlying mechanisms for effector Treg cell expansion in tumor are still unknown. We demonstrate that effector Treg cell-mediated suppression of antitumor CD8C T cells is tumor-nonspecific. Furthermore, TNFR2 expression is increased in these Treg cells by Affymetrix chip analysis which was confirmed by monoclonal antibody staining in both hepatocellular carcinoma (HCC) and colorectal cancer (CRC) patients and murine models. Correspondingly, increased levels of TNF-a in both tissue and serum were also demonstrated. Interestingly, TNF-a could not only expand effector Treg cells through TNFR2 signaling, but also enhanced their suppressive activity against antitumor immunity of CD8 C T cells. Furthermore, targeting TNFR2 signaling with a TNF-a inhibitor could selectively reduce rapid resurgence of effector Treg cells after cyclophosphamide-induced lymphodepletion and markedly inhibit the growth of established tumors. Herein, we propose a novel mechanism in which TNF-a could promote tumor-associated effector Treg cell expansion and suggest a new cancer immunotherapy strategy using TNF-a inhibitors to reduce effector Treg cells expansion after cyclophosphamide-induced lymphodepletion.

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Targeting regulatory T cells for improving cancer therapy: Challenges and prospects

Dwarakanath¹,

Farooque²,

Gupta

2018

Cancer Reports

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Objective: Regulatory T cells (Tregs) play a central role in immune responses to infectious agents and tumors. Paradoxically, Tregs protect self-cells from the immune response as a part of peripheral tolerance and prevents autoimmune disorders, whereas during the process of carcinogenesis, they are exploited by tumor cells for protection against antitumor immune responses. Therefore, Tregs are often considered as a major obstacle in anticancer therapy. The objective of this review is to provide a current understanding on Tregs as a potential cellular target for achieving therapeutic gain and discuss various approaches that are implicated at preclinical and clinical scenario.Recent findings: Several approaches like immunotherapy and adjuvant chemotherapy, which reduce Tregs population, have been found to be useful in improving local tumor control. Our recent observations with the glycolytic inhibitor, 2-deoxy-D-glucose, established as an adjuvant in radiotherapy and chemotherapy of tumors also show that potential of 2-deoxy-D-glucose to improve local tumor control is linked with its ability to reduce the Tregs pool.Conclusions: Several published studies and emerging evidences indicate that suppression of Treg numbers, infiltration into the tumors, and function can improve the cancer therapy by enhancing the antitumor immunity.

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Effector/Memory but Not Naive Regulatory T Cells Are Responsible for the Loss of Concomitant Tumor Immunity

Cited by 44 publications

References 48 publications

The Indispensable Role of CCR5 for In Vivo Suppressor Function of Tumor-Derived CD103+ Effector/Memory Regulatory T Cells

The Indispensable Role of CCR5 for In Vivo Suppressor Function of Tumor-Derived CD103+ Effector/Memory Regulatory T Cells

Blockade of TNF-α signaling benefits cancer therapy by suppressing effector regulatory T cell expansion

Targeting regulatory T cells for improving cancer therapy: Challenges and prospects

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