T-regulatory cell modulation: the future of cancer immunotherapy?

Nizar, Shiyam; Copier, John; Meyer, Brendan; Bodman‐Smith, Mark; Galustian, Christine; Kumar, Deepika; Dalgleish, Angus

doi:10.1038/sj.bjc.6605040

Cited by 85 publications

(69 citation statements)

References 51 publications

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“…Once we found that OX40 and CTLA-4 were highly expressed by tumor-specific Tregs at the tumor site, we decided erance (21) and to a worse prognosis (6,22) and probably explain many failures of cancer immunotherapy (4,23,24). Therefore, Tregs are now identified as a new target in the host that could be neutralized to reverse the suppressive effects of the tumor on the immune system (5,25,26). Tregs are usually identified by their expression of FOXP3.…”

Section: Discussionmentioning

confidence: 99%

Depleting tumor-specific Tregs at a single site eradicates disseminated tumors

Marabelle¹,

Kohrt²,

Sagiv-Barfi³

et al. 2013

J. Clin. Invest.

336

251

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Activation of TLR9 by direct injection of unmethylated CpG nucleotides into a tumor can induce a therapeutic immune response; however, Tregs eventually inhibit the antitumor immune response and thereby limit the power of cancer immunotherapies. In tumor-bearing mice, we found that Tregs within the tumor preferentially express the cell surface markers CTLA-4 and OX40. We show that intratumoral coinjection of anti-CTLA-4 and anti-OX40 together with CpG depleted tumor-infiltrating Tregs. This in situ immunomodulation, which was performed with low doses of antibodies in a single tumor, generated a systemic antitumor immune response that eradicated disseminated disease in mice. Further, this treatment modality was effective against established CNS lymphoma with leptomeningeal metastases, sites that are usually considered to be tumor cell sanctuaries in the context of conventional systemic therapy. These results demonstrate that antitumor immune effectors elicited by local immunomodulation can eradicate tumor cells at distant sites. We propose that, rather than using mAbs to target cancer cells systemically, mAbs could be used to target the tumor infiltrative immune cells locally, thereby eliciting a systemic immune response.

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Section: Discussionmentioning

confidence: 99%

Depleting tumor-specific Tregs at a single site eradicates disseminated tumors

Marabelle¹,

Kohrt²,

Sagiv-Barfi³

et al. 2013

J. Clin. Invest.

336

251

View full text Add to dashboard Cite

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“…A commonly used chemotherapeutic agent CY can selectively deplete Treg cells when administered more frequenty or "metronomically" at a dose substantially lower than the maximum tolerated dose. Such low-dose CY is not only immunostimulatory but also avoids CY high-dose toxicity (16,42). In addition, the restoration of Treg numbers and function 10 days after low-dose CY administration implies that a limited period of Treg cell inhibition may avoid potential autoimmunity (15).…”

Section: Discussionmentioning

confidence: 99%

Selective Depletion of CD4+CD25+Foxp3+ Regulatory T Cells by Low-Dose Cyclophosphamide Is Explained by Reduced Intracellular ATP Levels

Zhao

Cao²,

Zhang³

et al. 2010

Cancer Research

184

132

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CD4+ CD25 + Foxp3 + regulatory T (Treg) cells have been shown to play important roles in mediating cancer development. Although cyclophosphamide (CY) has shown promise as a drug to selectively target Treg cells with low-dose in vivo, the underlying molecular mechanism remains unclear. In this report, we provide evidence that ATP, the energy molecule and signal element, accounts for the selective depletion of Treg cells by low-dose CY. Relative to conventional T cells or other cell types, ATP levels were much lower in Treg cells. This was due to Treg cells that downregulate one microRNA, miR-142-3p, and upregulate ecto-nucleoside triphosphate diphosphohydrolase CD39. The transfection of miR-142-3p or the blockade of CD39 could increase intracellular ATP levels of Treg cells, consequently decreasing the sensitivity of Treg cells to low-dose CY. On the other hand, the transfection of miR-142-3p inhibitor or the addition of soluble CD39 to the cultured CD4 + CD25− T cells resulted in the decrease of intracellular ATP levels and increase of sensitivity of conventional T cells to low-dose CY. Furthermore, we found that the low levels of ATP attenuated the synthesis of glutathione, leading to the decrease of CY detoxification, thus increasing the sensitivity of Treg cells to low-dose CY. Therefore, we here identify a molecular pathway through which low-dose CY selectively ablates Treg cells. Our findings also imply that low levels of ATP are probably related to Treg cell function. Cancer Res; 70(12); 4850-8. ©2010 AACR.

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“…Immunotherapy for patients with colorectal cancer represents a realistic alternative approach to treatment of this disease [62][63][64] . The last 20 years has seen a wide range of publications on tumor immunity and the prognostic impact of immune and inflammatory cell types in the microenvironment of colorectal tumors demonstrating promising results both in vitro and in vivo.…”

Section: The Invasive Front Of Colorectal Cancer: Anti-tumor Factorsmentioning

confidence: 99%