Regulatory T cells in cancer immunosuppression — implications for anticancer therapy

Togashi, Yosuke; Shitara, Kohei; Nishikawa, Hiroyoshi

doi:10.1038/s41571-019-0175-7

Cited by 1,029 publications

(921 citation statements)

References 198 publications

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“…Checkpoint inhibitors such as PD‐1 and programmed cell death ligand‐1 (PD‐L1) together or combined with chemotherapy have been used as first‐ or second‐line therapy in treating solid tumors, such as lung cancer, and improving overall survival . The main mechanism is disrupting the tumor microenvironment and restoring T‐cell immune function . Similarly, PD‐1 inhibitors have been used for refractory and relapse lymphoma in clinical trials .…”

Section: Introductionmentioning

confidence: 99%

“…1,2 Increasing findings have shown that several immune checkpoint proteins play a key role in negatively regulating T-cell activation, including programmed cell death receptor- is disrupting the tumor microenvironment and restoring T-cell immune function. 8,9 Similarly, PD-1 inhibitors have been used for refractory and relapse lymphoma in clinical trials. 10 Recently, higher numbers of PD-1+ T cells have been reported in patients with leukemia, and PD-1 inhibitors have been shown to reverse T-cell immune escape and enhance T-cell cytotoxicity against AML in vitro and in an acute myeloid leukemia (AML) mouse model, as well as in clinical trials for AML and myelodysplastic syndrome (MDS).…”

Section: Introductionmentioning

confidence: 99%

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Higher frequency of the CTLA‐4⁺LAG‐3⁺ T‐cell subset in patients with newly diagnosed acute myeloid leukemia

Chen

Tan

Huang

et al. 2019

Asia-Pac J Clncl Oncology

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Aim Immune suppression based on alternative regulation of immune checkpoint proteins, for example, programmed cell death receptor‐1 (PD‐1) and cytotoxic T lymphocyte–associated molecule‐4 (CTLA‐4), which results in T‐cell exhaustion, contributes to cancer development and progression. In this study, we sought to characterize the distribution of CTLA‐4 and T‐cell lymphocyte activation gene‐3 (LAG‐3) expression on exhausted T cells in different T‐cell subsets from patients with acute myeloid leukemia (AML). Methods The coexpression of CTLA‐4 and LAG‐3 on exhausted CD244+ and CD57+ T cells from the CD3+, CD4+, and CD8+ T‐cell subsets in peripheral blood from 12 patients with newly diagnosed AML was analyzed by multicolor flow cytometry assay. Results A significantly higher percentage of CTLA‐4+CD3+, CD4+ and CD8+ T cells was found in patients with AML. In addition, higher numbers of both CTLA‐4+CD244+ and CTLA‐4+CD57+CD3+ T cells were detected. Interestingly, the increased CTLA‐4+CD244+ T cells were predominantly CD4+ T cells. In contrast, the increased CTLA‐4+CD57+ T cells primarily consisted of the CD8+ T‐cell subset. A high proportion of LAG‐3+ T cells was found in only a few cases with AML; however, a significantly higher proportion of coexpression of CTLA‐4 and LAG‐3 in the CD3+ and CD8+ T‐cell subsets was detected. Conclusion We for the first time observed higher CTLA‐4+CD244+CD4+, CTLA‐4+CD57+CD8+, CTLA‐4+LAG‐3+CD3+ and CTLA‐4+LAG‐3+CD8+ T cells in patients with AML, whereas the upregulated expression of LAG‐3 on T cells was only found in a subset of the cases. These data may provide further information by complementing the heterogeneity of immune checkpoints expression in AML.

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Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Higher frequency of the CTLA‐4⁺LAG‐3⁺ T‐cell subset in patients with newly diagnosed acute myeloid leukemia

Chen

Tan

Huang

et al. 2019

Asia-Pac J Clncl Oncology

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“…Our results also provide a rational basis for improving cancer immunotherapy in children. First, our data show that unlike adult cancer patients 63 , children with cancer do not have increased regulatory T-cells (SI Fig 9). Therefore, targeting these cells in children may not augment anti-tumor immunity.…”

Section: Lysis Of K562 Cells By Nk Cells From Four Of the Five Patienmentioning

confidence: 64%

Age related defects in NK cell immunity revealed by deep immune profiling of pediatric cancer patients

Syrimi

Khan

Murray

et al. 2020

Preprint

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Syrimi et al. High-Dimensional mass cytometry analysis reveals systemic immune perturbations in paediatric cancer influenced by ageOne Sentence Summary: High dimensional analysis of systemic immunity in pediatric cancer patients reveals clinically relevant immune changes in NK and T-cells that vary with patient age. Abstract:Systemic immunity plays important roles in cancer immune surveillance and therapy but little is known about the immune status of healthy children or children with cancer. We performed a high dimensional single cell analysis of systemic immunity in pediatric cancer patients and agematched healthy children. In young children with cancer (age <8years) NK cells were decreased in frequency, maturity, expression of perforin and granzyme-B, and were less cytotoxic in ex vivo assays. NK cell activity was restored after in vitro culture with interleukin-2. In contrast, older children with cancer (>8 years old) had decreased naive CD4 and CD8 T-cells with concomitant increases in effector memory and T effector memory RA-revertant (TEMRA) Tcells. These immunological changes in pediatric cancer patients are relevant to the better understanding of how cancers diagnosed in childhood interact with systemic immunity and could inform the development and application of effective immune-modulating therapies in the pediatric population. Syrimi et al. High-Dimensional mass cytometry analysis reveals systemic immune perturbations in paediatric cancer influenced by age

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“…Several Treg cell-targeted therapies are under investigation alone or in combination with ICBs. 1,52,53 Indeed, the anti-CTLA4 mAb ipilimumab can reinvigorate exhausted CD8 T cells while reportedly depleting Treg cells from the TME, which might contribute to the clinical benefits of this agent. [54][55][56][57] Yet, one possible concern with Treg cell-targeted therapy is that systemic Treg cell depletion might considerably increase the risk of immune-related adverse events, such as autoimmunity owing to systemic disruption of immune tolerance.…”

Section: Treg Cells To Inhibit Discrete Types Of T Cell Responses Itmentioning

confidence: 99%

“…[54][55][56][57] Yet, one possible concern with Treg cell-targeted therapy is that systemic Treg cell depletion might considerably increase the risk of immune-related adverse events, such as autoimmunity owing to systemic disruption of immune tolerance. 1,52 And several groups did observe an increased risk of colitis, rash and liver toxicity during the combined therapy of nivolumab with ipilimumab (an agent that can reportedly deplete or suppress Treg cells). 58,59 Mogamulizumab has also been associated with the development of rash and liver toxicity.…”

Section: Treg Cells To Inhibit Discrete Types Of T Cell Responses Itmentioning

confidence: 99%

Bcl6 Preserves the Suppressive Function of Regulatory T Cells during Tumorigenesis

Wang

Lin

et al. 2020

Preprint

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AbstractDuring tumorigenesis, tumor infiltrating regulatory T (Treg) cells restrict the function of effector T cells in tumor microenvironment and thereby promoting tumor growth. The anti-tumor activity of effector T cells can be therapeutically unleashed, and is now being exploited for the treatment of various types of human cancers. However, the immune suppressive function of Treg cells remains a major hurdle to broader effectiveness of tumor immunotherapy. In this article, we reported that the deletion of Bcl6 specifically in Treg cells led to stunted tumor growth, which was caused by impaired Treg cell responses. Notably, Bcl6 is essential in maintaining the lineage stability of Treg cells in tumor microenvironment. Meanwhile, we found that the absence of follicular regulatory T (Tfr) cells, which is a result of Bcl6 deletion in Foxp3+ cells, was dispensable for tumor control. Importantly, the increased Bcl6 expression in Treg cells is associated with poor prognosis of human colorectal cancer and lymph node metastasis of skin melanoma. Furthermore, Bcl6 deletion in Treg cells exhibits synergistic effects with immune checkpoint blockade therapy. Collectively, these results indicate that Bcl6 actively participates in regulating Treg cell immune responses during tumorigenesis and can be exploited as a therapeutic target of anti-tumor immunity.

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Regulatory T cells in cancer immunosuppression — implications for anticancer therapy

Cited by 1,029 publications

References 198 publications

Higher frequency of the CTLA‐4⁺LAG‐3⁺ T‐cell subset in patients with newly diagnosed acute myeloid leukemia

Higher frequency of the CTLA‐4⁺LAG‐3⁺ T‐cell subset in patients with newly diagnosed acute myeloid leukemia

Age related defects in NK cell immunity revealed by deep immune profiling of pediatric cancer patients

Bcl6 Preserves the Suppressive Function of Regulatory T Cells during Tumorigenesis

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Regulatory T cells in cancer immunosuppression — implications for anticancer therapy

Cited by 1,029 publications

References 198 publications

Higher frequency of the CTLA‐4+LAG‐3+ T‐cell subset in patients with newly diagnosed acute myeloid leukemia

Higher frequency of the CTLA‐4+LAG‐3+ T‐cell subset in patients with newly diagnosed acute myeloid leukemia

Age related defects in NK cell immunity revealed by deep immune profiling of pediatric cancer patients

Bcl6 Preserves the Suppressive Function of Regulatory T Cells during Tumorigenesis

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Higher frequency of the CTLA‐4⁺LAG‐3⁺ T‐cell subset in patients with newly diagnosed acute myeloid leukemia

Higher frequency of the CTLA‐4⁺LAG‐3⁺ T‐cell subset in patients with newly diagnosed acute myeloid leukemia