FOXP3+ Treg as a therapeutic target for promoting anti-tumor immunity

Whiteside, Theresa L.

doi:10.1080/14728222.2018.1451514

Cited by 136 publications

(97 citation statements)

References 116 publications

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“…PCC0208025 was synthetized as a white solid by biochempartner company (Shanghai, China) with the molecular formulae of C 25 The recombinant human PD-L1 protein (ab167713) was bought from Abcom company (USA) for studying the effects of PCC0208025 on IFN-γ secretion in human CD3 + cells in vitro. The human anti-PD-L1 antibody (BMS-936559) was expressed by Crown BioScience company (Suzhou, China).…”

Section: Drug and Reagentsmentioning

confidence: 99%

“…In tumors, Treg are viewed as anti-tumor suppressors, and can decrease anti-tumor immune responses [25]. Most Treg cells are defined based on CD4, CD25 and FOXP3 expression.…”

Section: Plos Onementioning

confidence: 99%

“…However, FOXP3 has a limited expression in Treg cells [25]. Recently, low level of CD127 on Treg cell surface are found, which is inversely correlated with FOXP3 level [25,26]. Thus, CD4 + CD25 + CD127 low/− can be the more reliable biomarker of Treg cells.…”

Section: Plos Onementioning

confidence: 99%

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PCC0208025 (BMS202), a small molecule inhibitor of PD-L1, produces an antitumor effect in B16-F10 melanoma-bearing mice

et al. 2020

PLoS ONE

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The increased PD-L1 expression induces poorer prognosis in melanoma. The small molecule inhibitors of PD-1/PD-L1 pathways have been an encouraging drug development strategy because of good affinity and oral bioavailability without immunogenicity and immunotoxicities of PD-1/PD-L1 antibodies. In this study, we studied the effects of PCC0208025 (BMS202), a small molecule inhibitor of PD-L1, on PD-1/PD-L1 binding and the cytokines secretion in human CD3 + cells in vitro. We also investigated the antitumor and immunomodulatory activity of PCC0208025 and the pharmacokinetics properties in B16-F10 melanoma-bearing mice. The results showed that PCC0208025 inhibited the PD-1/PD-L1 proteins binding, and rescued PD-L1-mediated inhibition of IFN-γ production in human CD3 + T cells in vitro. Furthermore, in B16-F10 melanoma-bearing mice, PCC0208025 presented the antitumor effects, enhanced IFN-γ levels in plasma, increased the frequency of CD3 + CD8 + T and CD8 + IFN-γ + T and the ratios of CD8 + /Treg, and deceased the CD4 + CD25 + CD127 low/− (Treg) number in tumor. Pharmacokinetics study found that PCC0208025 was absorbed and distributed into the tumors with much higher concentrations than those of the blockade against PD-1/PD-L1 binding. Our work suggests that PCC0208025 exhibited anti-tumor effects through inhibiting Treg expansion and increasing cytotoxic activity of tumor-infiltrating CD8 + T cells by the blockade of PD-1/PD-L1 binding, which may provide the pharmacological basis to develop small molecule inhibitors of PD-1/PD-L1 binding for PCC0208025 as a lead compound.

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Section: Drug and Reagentsmentioning

confidence: 99%

“…In tumors, Treg are viewed as anti-tumor suppressors, and can decrease anti-tumor immune responses [25]. Most Treg cells are defined based on CD4, CD25 and FOXP3 expression.…”

Section: Plos Onementioning

confidence: 99%

See 1 more Smart Citation

PCC0208025 (BMS202), a small molecule inhibitor of PD-L1, produces an antitumor effect in B16-F10 melanoma-bearing mice

et al. 2020

PLoS ONE

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“…Moreover, it is important to note that studies that showed the effect of ICI on T reg mainly used anti-CTLA-4 antibodies, and there are no available studies that showed a direct effect of anti-PD-1 antibodies on T reg function. T reg responses to ICI are complex and differ from other immune cell populations [28], and therefore warrant further investigations.…”

Section: Ic Expression On T Cells Have Multi-faceted Effects; Ic Exprmentioning

confidence: 99%

“…Targeting T reg through inhibition of suppressive function or recruitment to TME are plausible strategies to be used in combination with ICI to restore T reg : T eff ratios for clinical benefits [22]. T reg responses to ICI are complex and differ from other immune cell populations [28], and therefore warrant further investigations. However, a recent study on melanoma, prostate and bladder cancer patients showed that anti-CTLA-4 therapy does not deplete T reg populations [27].…”

Section: Ic Expression On T Cells Have Multi-faceted Effects; Ic Exprmentioning

confidence: 99%

Effect of pembrolizumab on CD4+CD25+, CD4+LAP+ and CD4+TIM-3+ T cell subsets

Toor

Nair

Pfister

et al. 2019

Clinical and Experimental Immunology

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Tumor immune evasion involves the expansion of avidly proliferating immunosuppressive cells and inhibition of effector T cell proliferation. Immune checkpoints (IC) block the activation pathways of tumor-reactive T cells. IC pathways are often exploited by tumor cells to evade immune destruction, and blocking these pathways through IC inhibitors (ICI) has shown promising results in multiple malignancies. In this study, we investigated the effects of an ICI, pembrolizumab, on various T cell subsets in vitro. We compared the suppressive activity of CD4 + CD25 + regulatory T cells (conventional T reg ) with T cells expressing T cell immunoglobulin-3 + (TIM-3 + ) and latency-associated peptide (LAP) + T cells. We found that LAP-expressing T cells were more suppressive than conventional T reg , but TIM-3-expressing T cells were not suppressive. Our results show that pembrolizumab does not modulate functions of T reg and mediates its immunostimulatory effects via the release of effector T cells from sup-pression. These findings may assist in the development of agents designed to intervene in IC pathways to overcome T reg resistance to ICI.

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NOX2 Enzyme Mimicking Nano‐Networks Regulate Tumor‐Associated Macrophages to Initiate Both Innate and Adaptive Immune Effects

Zhang,

Yin,

Zhao

et al. 2024

Adv Healthcare Materials

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Macrophages, capable of both direct killing and antigen presentation, are crucial for the interplay between innate and adaptive immunity. However, strategies mainly focus on polarizing tumor‐associated macrophages (TAMs) to M1 phenotype, while overlooking the inefficient antigen cross‐presentation due to hyperactive hydrolytic protease within lysosomes which leads to antigen degradation. In light of the significant influence of reactive oxygen species (ROS) on TAMs' polarization and the inhibition of phagosomal proteolysis, a novel nanosystem termed OVA‐Fe‐GA (OFG) is engineered, drawing inspiration from the NOX2 enzyme's role. OFG integrates ovalbumin (OVA) and a network composed of Fe‐gallic acid (GA), emulating the NOX2 enzyme's sequential ROS generation process (“O2 to O2•− to H2O2/•OH”). Furthermore, it elucidates a biological mechanism that augments antigen cross‐presentation by suppressing the expression of cysteine proteases. OFG restores the innate anti‐tumor functionality of TAMs and significantly amplifies their antigen cross‐presentation (4.5‐fold compared to the PBS control group) in B16‐OVA tumor‐bearing mice. Notably, the infiltration and activity of intratumoral CD8+ T cells are enhanced, indicating an adaptive immune response. Moreover, OFG exhibits excellent photothermal properties, thereby fostering a system antitumor immune response. This study provides a promising strategy for initiating both innate and adaptive immunity via TAMs activation.This article is protected by copyright. All rights reserved

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FOXP3+ Treg as a therapeutic target for promoting anti-tumor immunity

Cited by 136 publications

References 116 publications

PCC0208025 (BMS202), a small molecule inhibitor of PD-L1, produces an antitumor effect in B16-F10 melanoma-bearing mice

PCC0208025 (BMS202), a small molecule inhibitor of PD-L1, produces an antitumor effect in B16-F10 melanoma-bearing mice

Effect of pembrolizumab on CD4+CD25+, CD4+LAP+ and CD4+TIM-3+ T cell subsets

NOX2 Enzyme Mimicking Nano‐Networks Regulate Tumor‐Associated Macrophages to Initiate Both Innate and Adaptive Immune Effects

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