CTLA-4 blockade enhances polyfunctional NY-ESO-1 specific T cell responses in metastatic melanoma patients with clinical benefit

Yuan, Jianda; Gnjatic, Sacha; Li, Hao; Powel, Sarah; Gallardo, Humilidad F.; Ritter, Erika; Ku, Geoffrey Yuyat; Jungbluth, Achim A.; Segal, Neil H.; Rasalan, Teresa; Manukian, Gregor; Xu, Yinyan; Román, Ruth; Terzulli, Stephanie; Heywood, Melanie; Pogoriler, E.; Ritter, Gerd; Old, Lloyd J.; Allison, James P.; Wolchok, Jedd D.

doi:10.1073/pnas.0810114105

Cited by 320 publications

(261 citation statements)

References 32 publications

(35 reference statements)

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“…These kind of double producers are well known to control tumor progression in mice and men. 5,6,39,40 Collectively, these results show that CTLA-4 deficiency in vivo or absence of CTLA-4 signals in vitro enhances the functional and transcriptional plasticity of Tc17 cells and thus profoundly augments their antitumor activity.…”

Section: Ctla-4 Restricts the Cytotoxic Function Of Tc17 Cellsmentioning

confidence: 81%

“…44 It is likely that this mechanism occurs in response to anti-CTLA-4 therapy (Ipilimumab) in melanoma patients. 5,6 In addition, strategies that enhance the plasticity of Tc17 cells in tumor-bearing subjects and the development of Tc1-like cytokine patterns have been shown to result in stronger antitumor immunity due to increased cell persistence and cytotoxicity. 20,21 Efforts to inhibit Tc17 cell activity are likely to result in a valuable strategy for treating cancer; 52 indeed, CTLA-4 blockade is well known to augment the antitumor activity of T cells in patients with advanced melanoma.…”

Section: Discussionmentioning

confidence: 99%

“…3 In mice and humans, Tc1 cells coexpressing two or three of their signature cytokines are correlated with reduced bacterial load and tumor burden. [4][5][6] Nevertheless, depending on the activation conditions, a cytokine milieu containing transforming growth factor b (TGF-b) and IL-6 7,8 drives CD8 C T cells to differentiate into IL-17-producing Tc17 cells, which have only limited cytotoxic activity. 9 In addition to TCR and co-stimulation-mediated signals, a third signal provided by cytokine receptor engagement with its respective cytokine, strongly determines the outcome of T cell differentiation as well as the stability of the initial phenotype.…”

Section: Introductionmentioning

confidence: 99%

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The differentiation and plasticity of Tc17 cells are regulated by CTLA-4-mediated effects on STATs

et al. 2017

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As the blockade of inhibitory surface-molecules such as CTLA-4 on T cells has led to recent advances in antitumor immune therapy, there is great interest in identifying novel mechanisms of action of CD8 C T cells to evoke effective cytotoxic antitumor responses. Using in vitro and in vivo models, we investigated the molecular pathways underlying the CTLA-4-mediated differentiation of IL-17-producing CD8 C T cells (Tc17 cells) that strongly impairs cytotoxicity. Our studies demonstrate that Tc17 cells lacking CTLA-4 signaling have limited production of STAT3-target gene products such as IL-17, IL-21, IL-23R and RORgt. Upon re-stimulation with IL-12, these cells display fast downregulation of Tc17 hallmarks and acquire Tc1 characteristics such as IFNg and TNF-a co-expression, which is known to correlate with tumor control. Indeed, upon adoptive transfer, these cells were highly efficient in the antigen-specific rejection of established OVA-expressing B16 melanoma in vivo. Mechanistically, in primary and re-stimulated Tc17 cells, STAT3 binding to the IL-17 promoter was strongly augmented by CTLA-4, associated with less binding of STAT5 and reduced relative activation of STAT1 which is known to block STAT3 activity. Inhibiting CTLA-4-induced STAT3 activity reverses enhancement of signature Tc17 gene products, rendering Tc17 cells susceptible to conversion to Tc1-like cells with enhanced cytotoxic potential. Thus, CTLA-4 critically shapes the characteristics of Tc17 cells by regulating relative STAT3 activation, which provides new perspectives to enhance cytotoxicity of antitumor responses.

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Section: Ctla-4 Restricts the Cytotoxic Function Of Tc17 Cellsmentioning

confidence: 81%

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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The differentiation and plasticity of Tc17 cells are regulated by CTLA-4-mediated effects on STATs

et al. 2017

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“…CTLA-4 is upregulated during T-cell activation and causes competitive inhibition of B7-CD28 induced T-cell activation, modulates intracellular signalling pathways and leads to decreased IL-2 production, impaired T-cell receptor signalling and cell-cycle arrest, particularly in the early post-activation phase (Hodi, 2007). Anti-CTLA-4 treatment has been trialled in melanoma and other cancers with some evidence of clinical efficacy (Wolchok and Saenger, 2008;Yuan et al, 2008). The expression of PD-L1 (B7-H1), a ligand for PD-1, is upregulated by IFN-g (Blank et al, 2004) and has been observed in many tumour types, often being associated with a poor prognosis (Zou and Chen, 2008).…”

Section: Activated T Cells May Be Switched Off By Some Tumoursmentioning

confidence: 99%

“…Failure of the anti-tumour immune response can occur at one or more of these steps. Targeting ratelimiting steps with therapies designed to boost the immune response can improve anti-tumour immunity (Yuan et al, 2008). In addition to specifically targeted immune therapies, it is also now clear that many traditional cancer therapies can improve key aspects of anti-cancer immunity by inducing tumour cell death in a way that is immunostimulatory or by modulating tumourinduced immunosuppression .…”

Section: Introductionmentioning

confidence: 99%

Harnessing the immune response to treat cancer

et al. 2010

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It is well established that the immune system has the capacity to attack malignant cells. During malignant transformation cells acquire numerous molecular and biochemical changes that render them potentially vulnerable to immune cells. Yet it is self-evident that a growing tumour has managed to evade these host defence mechanisms. The exact ways in which the immune system interacts with tumour cells and how cancers are able to escape immunological eradication have only recently started to be fully elucidated. Understanding the relationship between the tumour and the anti-tumour immune response and how this can be altered with conventional treatments and immune-targeted therapies is crucial to developing new treatments for patients with cancer. In this review, focusing on the anti-tumour T-cell response, we summarize our understanding of how tumours, cancer treatments and the immune system interact, how tumours evade the immune response and how this process could be manipulated for the benefit of patients with cancer.

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Co‐Administration of Co‐Stimulatory Moieties

Latchman

Arancibia

2012

Vaccinology

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CTLA-4 blockade enhances polyfunctional NY-ESO-1 specific T cell responses in metastatic melanoma patients with clinical benefit

Cited by 320 publications

References 32 publications

The differentiation and plasticity of Tc17 cells are regulated by CTLA-4-mediated effects on STATs

The differentiation and plasticity of Tc17 cells are regulated by CTLA-4-mediated effects on STATs

Harnessing the immune response to treat cancer

Co‐Administration of Co‐Stimulatory Moieties

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