Responsiveness of HIV-specific CD4 T cells to PD-1 blockade

Porichis, Filippos; Kwon, Douglas S.; Zupkosky, Jennifer; Tighe, Daniel P.; McMullen, Ashley; Brockman, Mark A.; Pavlik, David F.; Rodriguez-García, Marta; Pereyra, Florencia; Freeman, Gordon J.; Kavanagh, Daniel G.; Kaufmann, Daniel E.

doi:10.1182/blood-2010-12-328070

Cited by 145 publications

(154 citation statements)

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“…Interestingly, in vitro stimulation was required to see the beneficial effects of PD-1 blockade in terms of cytokine secretion, suggesting that PD-1 blockade was promoting the expansion of functional T cells rather than restoring function to fully exhausted T cells. Other studies, however, noted that cytokine production could be elevated immediately after PD-1 blockage, suggesting that PD-1 and PD-L1 interactions were the primary cause of the lack of cytokine production (42,43). Studying the effects of PD-1 blockade in restoring function to tumor-specific T cells also has resulted in inconsistent and conflicting data.…”

Section: Discussionmentioning

confidence: 90%

Strength of PD-1 signaling differentially affects T-cell effector functions

Wei

Shi

et al. 2013

Proc. Natl. Acad. Sci. U.S.A.

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High surface expression of programmed death 1 (PD-1) is associated with T-cell exhaustion; however, the relationship between PD-1 expression and T-cell dysfunction has not been delineated. We developed a model to study PD-1 signaling in primary human T cells to study how PD-1 expression affected T-cell function. By determining the number of T-cell receptor/peptide-MHC complexes needed to initiate a Ca 2+ flux, we found that PD-1 ligation dramatically shifts the dose-response curve, making T cells much less sensitive to T-cell receptor-generated signals. Importantly, other T-cell functions were differentially sensitive to PD-1 expression. We observed that high levels of PD-1 expression were required to inhibit macrophage inflammatory protein 1 beta production, lower levels were required to block cytotoxicity and IFN-γ production, and very low levels of PD-1 expression could inhibit TNF-α and IL-2 production as well as T-cell expansion. These findings provide insight into the role of PD-1 expression in enforcing T-cell exhaustion and the therapeutic potential of PD-1 blockade.

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Section: Discussionmentioning

confidence: 90%

Strength of PD-1 signaling differentially affects T-cell effector functions

Wei

Shi

et al. 2013

Proc. Natl. Acad. Sci. U.S.A.

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251

184

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“…Furthermore, PD-1 is significantly up-regulated in exhausted virus-specific CD4 ϩ T cells during HIV and CMV infections, and blocking activation of PD-1 was shown to partially restore T-cell function. [38][39][40] Furthermore, a recent study by Yang et al further provides evidence for the existence of exhausted FL TIL subsets, induced by IL-12 via up-regulation of TIM-3. 41 The TIM-3 ϩ cells were unresponsive to the cytokines IFN-␥, IL-6, and IL-12 and had intermediate expression of PD-1.…”

Section: Discussionmentioning

confidence: 99%

High PD-1 expression and suppressed cytokine signaling distinguish T cells infiltrating follicular lymphoma tumors from peripheral T cells

Myklebust

Irish

Brody

et al. 2013

Blood

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Key Points• FL TILs have reduced cytokine signaling. FL outcome is strongly influenced by the immune cell microenvironment. Gene expression profiling has identified a clinically relevant gene expression signature that possibly represents an immune response to the tumor. 1 Furthermore, the immune cell composition of the FL tumor microenvironment is important because high numbers of tissue-infiltrating macrophages correlated with poor outcome in patients receiving chemotherapy regimens, 2 but not in patients also receiving the monoclonal antibody rituximab. 3,4 Several observations further support the hypothesis of an immune suppressive microenvironment in affected lymph nodes (LNs). These LNs have increased numbers of T regulatory cells (Tregs), 5,6 and purified FL lymphoma B cells can induce the conversion of conventional CD4 ϩ T cells into FoxP3 ϩ Tregs. [5][6][7][8] Most studies have found a positive correlation between the number of infiltrating Tregs and favorable outcome, 9-11 although some report opposite findings. 12 However, follicular localization of Tregs was then found to be associated with poor overall survival and high risk of transformation. 13 A recent study further implied that tumor-infiltrating T cells (TILs) from FL biopsies had impaired immunologic synapse formation. 14 Phospho-flow cytometric analysis has emerged as a powerful tool to analyze intracellular signaling events in complex populations of cells, because of its ability to simultaneously discriminate cell types on the basis of surface marker expression and to assess the activation status of intracellular proteins. [15][16][17][18] We used this method and identified a new lymphoma subset in patients with FL, the lymphoma-negative prognostic subset, with abnormal B-cell antigen receptor signaling. 19 Strikingly, the prevalence of this lymphoma cell subset in patient's tumor at the time of diagnosis, before any treatment, was negatively associated both with the response to initial chemotherapy and with overall survival. The patients' T-cell responses were also important, because patients with high IL-7-induced phosphorylation of STAT5 in TILs had a better outcome. 19 We therefore expanded on this observation by interrogating the responsiveness of FL TILs to a variety of effector Submitted April 12, 2012; accepted December 3, 2012. Prepublished online as Blood First Edition paper, January 7, 2013; DOI 10.1182/blood-2012-04-421826. Defects in T-cell function in patients withThe online version of this article contains a data supplement.The publication costs of this article were defrayed in part by page charge payment. Therefore, and solely to indicate this fact, this article is hereby marked ''advertisement'' in accordance with 18 USC section 1734. Here, using phospho-flow cytometry, we found that FL TILs had distinctively reduced signaling responses to several cytokines, including IL-4, IL-10, and IL-21. We identified that CD4 ϩ CD45RO ϩ CD62L Ϫ T cells, the main T-cell subset in FL LNs, was largely unresponsive to cytokines, exemplified ...

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“…In contrast to the significant progress made in understanding mechanisms of CD8 T cell exhaustion, CD4 T cell dysfunction remains much less explored. Data demonstrate both similarities and major differences in the exhaustion mechanisms mediating exhaustion of these cell subsets (2,3). In HIV-1 infection, studies by our group (2,3) and others (4,5) have shown that PD-1 is upregulated on virus-specific CD4 T cells and mediates a dysfunction that is reversible upon PD-1 blockade in vitro.…”

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confidence: 99%