Fc-dependent depletion of tumor-infiltrating regulatory T cells co-defines the efficacy of anti–CTLA-4 therapy against melanoma

Simpson, Tyler R.; Li, Fubin; Montalvo-Ortiz, Welby; Sepúlveda, Manuel A.; Bergerhoff, Katharina; Arce, Frederick; Roddie, Claire; Henry, Jake Y.; Yagita, Hideo; Wolchok, Jedd D.; Peggs, Karl S.; Ravetch, Jeffrey V.; Allison, James P.; Quezada, Sergio A.

doi:10.1084/jem.20130579

Cited by 1,267 publications

(1,191 citation statements)

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“…Moreover, CTLA-4 inhibition lowers the threshold required for T cell activation, which results in increased expansion and diversification of circulating, low-avidity T cells 33 ; it also causes an Fc-γR-mediated depletion of T reg cells 34 . In agreement with this, treatment with ipilimumab was found to broaden the TCR repertoire more robustly, within 2 weeks, in those experiencing irAEs than in those without irAEs, and treatment response improved along with the increase in TCR diversity.…”

Section: Autoimmune Consequencesmentioning

confidence: 99%

Is autoimmunity the Achilles' heel of cancer immunotherapy?

June

Warshauer

Bluestone

2017

Nat Med

388

308

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Section: Autoimmune Consequencesmentioning

confidence: 99%

Is autoimmunity the Achilles' heel of cancer immunotherapy?

June

Warshauer

Bluestone

2017

Nat Med

388

308

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“…CTLA-4 is known to be upregulated on all effector T cells and is also expressed on all Tregs. Consequently, blockade of CTLA-4 could disrupt CTLA-4-driven regulation of effector T-cell responses or interfere with the function and/or number of Tregs, as has been suggested by recent studies (30)(31)(32). Indeed, autoimmune-like toxicities are commonly observed in patients treated with anti-CTLA-4 antibody (1).…”

Section: Distinguishing Features Of Tim-3mentioning

confidence: 97%

Tim-3: An Emerging Target in the Cancer Immunotherapy Landscape

Anderson

2014

Cancer Immunology Research

273

186

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The cancer immunotherapy field has grown exponentially in the past few years, largely driven by the success of immune checkpoint blockade. Therapies targeting the immune checkpoint molecules CTLA-4 and PD-1 have achieved objective responses in melanoma, renal cancer, and lung cancer; however, a large number of patients are still suffering with these cancers that are not benefiting from these therapies. Moreover, several cancers have proved to be largely refractory to therapies that target CTLA-4 and PD-1. This has catalyzed interest in targeting novel immune checkpoint receptors with the goal of realizing the full potential of checkpoint blockade for treating cancer. In this regard, the immune checkpoint receptor Tim-3 exhibits several unique features that make it an intriguing candidate for the next wave of therapies that target immune checkpoints in cancer. Cancer Immunol Res; 2(5); 393-8. Ó2014 AACR.

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“…Although anti-CT-LA-4 mAb was first suggested to augment the activity of tumor-infiltrating CD8 + and CD4 + T cells, recent studies have suggested another possibility that anti-CTLA-4 mAb predominantly affects Treg cells, thereby enhancing anti-tumor immune responses. Using Fc receptor-deficient mice, the anti-tumor activity of anti-CTLA-4 mAb was shown to be dependent on antibody-dependent cellular cytotoxicity of Treg cells in tumor tissues instead of affecting re-activation of Tconv cells [61][62][63]. In cancer patients, strong correlations have been reported between the clinical efficacy of Ipilimumab and reduction of Treg cell numbers in tumor tissues [64][65].…”

Section: Checkpoint Blockade Antibody With Possible Treg-depleting Efmentioning

confidence: 99%