PD-1 Blockade Augments Th1 and Th17 and Suppresses Th2 Responses in Peripheral Blood From Patients With Prostate and Advanced Melanoma Cancer

Dulos, John; Carven, Gregory J.; Boxtel, Susan J. van; Evers, Sabine; Driessen-Engels, Lilian J. A.; Hobo, Willemijn; Górecka, Monika; Haan, A.F.J. de; Mulders, Peter F.A.; Punt, Cornelis J. A.; Jacobs, Joannes F M; Schalken, Jack A.; Oosterwijk, Egbert; Eenennaam, Hans van; Boots, A.

doi:10.1097/cji.0b013e318247a4e7

Cited by 266 publications

(185 citation statements)

References 43 publications

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“…Similarly, augmentation of Th1 cytokines was observed in patients treated with PD-1 blockade (41). ATT with PD-1:28 tm -positive T cells also resulted in more IL10, which may enhance cytotoxicity and IFNg secretion by CD8 þ T cells and tumor growth, but may also suppress antitumor immunity (42,43). Despite positive effects of PD-1:28 tm on T-cell performance in ATT, this was not sufficient to change tumor growth characteristics in this murine tumor model.…”

Section: Discussionmentioning

confidence: 89%

Chimeric PD-1:28 Receptor Upgrades Low-Avidity T cells and Restores Effector Function of Tumor-Infiltrating Lymphocytes for Adoptive Cell Therapy

et al. 2017

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Inherent intermediate-to low-affinity T-cell receptors (TCR) that develop during the natural course of immune responses may not allow sufficient activation for tumor elimination, making the majority of T cells suboptimal for adoptive T-cell therapy (ATT). TCR affinity enhancement has been implemented to provide stronger T-cell activity but carries the risk of creating undesired cross-reactivity leading to potential serious adverse effects in clinical application. We demonstrate here that engineering of low-avidity T cells recognizing a naturally processed and presented tumor-associated antigen with a chimeric PD-1:28 receptor increases effector function to levels seen with high-avidity T cells of identical specificity. Upgrading the function of low-avidity T cells without changing the TCR affinity will allow a large arsenal of low-avidity T cells previously thought to be therapeutically inefficient to be considered for ATT. PD-1:28 engineering reinstated Th1 function in tumor-infiltrating lymphocytes that had been functionally disabled in the human renal cell carcinoma environment without unleashing undesired Th2 cytokines or IL10. Involved mechanisms may be correlated to restoration of ERK and AKT signaling pathways. In mouse tumor models of ATT, PD-1:28 engineering enabled low-avidity T cells to proliferate stronger and prevented PD-L1 upregulation and Th2 polarization in the tumor milieu. Engineered T cells combined with checkpoint blockade secreted significantly more IFNg compared with T cells without PD-1:28, suggesting a beneficial combination with checkpoint blockade therapy or other therapeutic strategies. Altogether, the supportive effects of PD-1:28 engineering on T-cell function make it an attractive tool for ATT. Cancer Res; 77(13); 3577-90. Ó2017 AACR.

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Section: Discussionmentioning

confidence: 89%

Chimeric PD-1:28 Receptor Upgrades Low-Avidity T cells and Restores Effector Function of Tumor-Infiltrating Lymphocytes for Adoptive Cell Therapy

et al. 2017

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“…Recent clinical data reported augmentation of Th1 and Th17 responses in patients treated with anti-PD-1 therapy (42). Also, mesenchymal stem cells suppress Th17 proliferation via PD-L1 expression, and IL-27-primed CD4 + T cells inhibit Th17 cell differentiation via PD-L1 (43).…”

Section: Discussionmentioning

confidence: 99%

Programmed Death-1 Pathway in Host Tissues Ameliorates Th17/Th1-Mediated Experimental Chronic Graft-versus-Host Disease

Fujiwara

Maeda

Kobayashi

et al. 2014

The Journal of Immunology

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Chronic graft-versus-host disease (GVHD) is a major cause of late death and morbidity after allogeneic hematopoietic cell transplantation, but its pathogenesis remains unclear. We investigated the role of the programmed death-1 (PD-1) pathway in chronic GVHD using a well-defined mouse model of B10.D2 (H-2d) donor to BALB/c (H-2d) recipients. PD-1 expression on allogeneic donor T cells was upregulated continuously in chronic GVHD development, whereas PD-L1 expression in host tissues was transiently upregulated and declined to basal levels in the late posttransplant period. Blockade of the PD-1 pathway by anti–PD-1, anti–PD-L1, or anti–PD-L2 mAbs exacerbated clinical and pathologic chronic GVHD. Chimeric mice revealed that PD-L1 expression in host tissues suppressed expansion of IL-17+IFN-γ+ T cells, and that PD-L1 expression on hematopoietic cells plays a role in the development of regulatory T cells only during the early transplantation period but does not affect the severity of chronic GVHD. Administration of the synthetic retinoid Am80 overcame the IL-17+IFN-γ+ T cell expansion caused by PD-L1 deficiency, resulting in reduced chronic GVHD damage in PD-L1−/− recipients. Stimulation of the PD-1 pathway also alleviated chronic GVHD. These results suggest that the PD-1 pathway contributes to the suppression of Th17/Th1-mediated chronic GVHD and may represent a new target for the prevention or treatment of chronic GVHD.

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“…In fact, there is evidence that shows skewing towards a Th1/Th17 response in advanced cancer [70]. However, other reports show that the therapeutic improvements are modest [80] and in some cases restricted to antigen presentation in the context of minor histocompatibility complexes [63].…”

Section: Application Of Pd-l1/pd-1 Blockade In Clinical Trialsmentioning

confidence: 95%

“…However, this has been tested in the context of superantigen stimulation or recall responses towards tetanus toxoid [70]. In this way, possibly already "committed" memory T cells could be activated.…”

Section: Blocking Pd-l1/pd-1 Negative Co-stimulation May Commit T Celmentioning

confidence: 99%

Signaling Mechanisms that Balance Anti-viral, Auto-reactive, and Antitumor Potential of Low Affinity T Cells

Hebeisen¹,

Rufer²,

Oberle³

et al. 2013

J Clin Cell Immunol

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For T cell activation, three signals have to be provided from the antigen presenting cell; Signal 1 (antigen recognition), signal 2 (co-stimulation) and signal 3 (cytokine priming). Blocking negative co-stimulation during antigen presentation to T cells is becoming a promising therapeutic strategy to enhance cancer immunotherapy. Here we will focus on interference with PD-1/PD-L1 negative co-stimulation during antigen presentation to T cells as a therapeutic approach. We will discuss the potential mechanisms and the therapeutic consequences by which interference/inhibition with this interaction results in anti-tumour immunity. Particularly, we will comment on whether blocking negative co-stimulation provides differentiation signals to T cells undergoing antigen presentation. A major dogma in immunology states that T cell differentiation signals are given by cytokines and chemokines (signal 3) rather than co-stimulation (signal 2). We will discuss whether this is the case when blocking PD-L1/PD-1 negative co-stimulation.

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PD-1 Blockade Augments Th1 and Th17 and Suppresses Th2 Responses in Peripheral Blood From Patients With Prostate and Advanced Melanoma Cancer

Cited by 266 publications

References 43 publications

Chimeric PD-1:28 Receptor Upgrades Low-Avidity T cells and Restores Effector Function of Tumor-Infiltrating Lymphocytes for Adoptive Cell Therapy

Chimeric PD-1:28 Receptor Upgrades Low-Avidity T cells and Restores Effector Function of Tumor-Infiltrating Lymphocytes for Adoptive Cell Therapy

Programmed Death-1 Pathway in Host Tissues Ameliorates Th17/Th1-Mediated Experimental Chronic Graft-versus-Host Disease

Signaling Mechanisms that Balance Anti-viral, Auto-reactive, and Antitumor Potential of Low Affinity T Cells

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