Secretion of human soluble programmed cell death protein 1 by chimeric antigen receptor-modified T cells enhances anti-tumor efficacy

Abstract Background The immune checkpoint receptor programmed cell death protein I (PD-1) has been identified as a key target in immunotherapy. PD-1 reduces the risk of autoimmunity by inducing apoptosis in antigen-specific T cells upon interaction with programmed cell death protein ligand I (PD-L1). Various cancer types overexpress PD-L1 to evade the immune system by inducing apoptosis in tumor-specific CD8+ T cells. The clinically used blocking antibody nivolumab binds to PD-1 and inhibits the immunosuppressive interaction with PD-L1. Even though PD-1 is already used as a drug target, the exact mechanism of the receptor is still a matter of debate. For instance, it is hypothesized that the signal transduction is based on an active conformation of PD-1. Results Here we present the results of the first molecular dynamics simulations of PD-1 with a complete extracellular domain with a focus on the role of the BC-loop of PD-1 upon binding PD-L1 or nivolumab. We could demonstrate that the BC-loop can form three conformations. Nivolumab binds to the BC-loop according to the conformational selection model whereas PD-L1 induces allosterically a conformational change of the BC-loop. Conclusion Due to the structural differences of the BC-loop, a signal transduction based on active conformation cannot be ruled out. These findings will have an impact on drug design and will help to refine immunotherapy blocking antibodies.

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The role of the programmed cell death protein-1/programmed death-ligand 1 pathway, regulatory T cells and T helper 17 cells in tumor immunity: a narrative review

Annals of Translational Medicine ◽

10.21037/atm-20-6719 ◽

2020 ◽

Vol 8 (22) ◽

pp. 1526-1526

Author(s):

Lanfang Zhang ◽

Mingjuan Zhang ◽

Jinxiu Xu ◽

Shan Li ◽

Yu Chen ◽

...

Keyword(s):

T Cells ◽

Cell Death ◽

Programmed Cell Death ◽

T Helper ◽

T Helper 17 ◽

T Helper 17 Cells ◽

Programmed Death Ligand 1 ◽

Programmed Death ◽

Cell Death Protein

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Prior irradiation results in elevated programmed cell death protein 1 (PD-1) in T cells

International Journal of Radiation Biology ◽

10.1080/09553002.2017.1400192 ◽

2017 ◽

Vol 94 (5) ◽

pp. 488-494 ◽

Cited By ~ 13

Author(s):

Deguan Li ◽

Renxiang Chen ◽

Yi-Wen Wang ◽

Albert J. Fornace ◽

Heng-Hong Li

Keyword(s):

T Cells ◽

Cell Death ◽

Programmed Cell Death ◽

Cell Death Protein

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Anti-CD3 treatment up-regulates programmed cell death protein-1 expression on activated effector T cells and severely impairs their inflammatory capacity

Immunology ◽

10.1111/imm.12729 ◽

2017 ◽

Vol 151 (2) ◽

pp. 248-260 ◽

Cited By ~ 11

Author(s):

Maja Wallberg ◽

Asha Recino ◽

Jenny Phillips ◽

Duncan Howie ◽

Margaux Vienne ◽

...

Keyword(s):

T Cells ◽

Cell Death ◽

Programmed Cell Death ◽

Effector T Cells ◽

Cell Death Protein

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Maprotiline Prompt the Anti-tumor Effect by Inhibiting the PD-L1 in Mice Burdened Melanoma

10.21203/rs.3.rs-1172486/v1 ◽

2021 ◽

Author(s):

Tiesuo Zhao ◽

Yang Li ◽

Miaomiao Liu ◽

Lin Zhou ◽

Zunge Wu ◽

...

Keyword(s):

Immune Response ◽

T Cells ◽

Cell Death ◽

Programmed Cell Death ◽

Tumor Tissues ◽

Programmed Cell Death 1 ◽

Tetracyclic Antidepressant ◽

And Migration ◽

Cell Death Protein

Abstract Programmed cell death 1 ligand 1(PD-L1) binds with programmed cell death protein 1 (PD-1) to inhibit the responses of T cells. PD-L1 is significantly upregulated on tumor cells and blocking the PD-L1/PD-1 signal has become an important target of immunotherapy in clinic. At present, some old drugs of non-antitumor have been found that could play the effect of anti-tumor. Maprotiline, as a tetracyclic antidepressant, has been widely used for treating mental depression. Here, we study the anti-tumor effect of maprotiline by strengthening the immune response of mice. In vitro, treatment with maprotiline inhibits the proliferation and migration of B16 cells, increases the cell apoptosis. Importantly, treatment with maprotiline reduces the expression of PD-L1 in tumor tissue, prompts the ratios of CD4+ T cells, CD8+ T cells and NK cells in spleens, increases the infiltration of CD4+ and CD8+ T cells in tumor-tissues. In brief, we determine that maprotiline could prompt the anti-tumor immune response by inhibiting the PD-L1 in mice. This study may find a new inhibitor of PD-L1, which provides a new drug treated tumor in clinical.

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Immune checkpoint dysfunction in large and medium vessel vasculitis

AJP Heart and Circulatory Physiology ◽

10.1152/ajpheart.00024.2017 ◽

2017 ◽

Vol 312 (5) ◽

pp. H1052-H1059 ◽

Cited By ~ 37

Author(s):

Ryu Watanabe ◽

Hui Zhang ◽

Gerald Berry ◽

Jörg J. Goronzy ◽

Cornelia M. Weyand

Keyword(s):

T Cells ◽

Cell Death ◽

T Cell ◽

Programmed Cell Death ◽

Immune Checkpoint ◽

Intimal Hyperplasia ◽

Cd4 T Cells ◽

Vessel Wall ◽

Checkpoint Inhibitors ◽

Cell Death Protein

Giant cell arteritis (GCA) is a granulomatous vasculitis of the aorta and its medium-sized branch vessels. CD4 T cells, macrophages, and dendritic cells (DCs) build granulomatous infiltrates that injure the vessel wall and elicit a maladaptive response to injury. Pathological consequences include fragmentation of elastic membranes, destruction of the medial layer, microvascular neoangiogenesis, massive outgrowth of myofibroblasts, and lumen-occlusive intimal hyperplasia. Antigens have been suspected to drive the local activation of vasculitogenic CD4 T cells, but recent data have suggested a more generalized defect in the threshold setting of such T cells, rendering them hyperreactive. Under physiological conditions, immune checkpoints provide negative signals to curb T cell activation and prevent inflammation-associated tissue destruction. This protective mechanism is disrupted in GCA. Vessel wall DCs fail to express the immunoinhibitory ligand programmed cell death ligand-1, leaving lesional T cells unchecked. Consequently, programmed cell death protein-1-positive CD4 T cells can enter the immunoprivileged vessel wall, where they produce a broad spectrum of inflammatory cytokines (interferon-γ, IL-17, and IL-21) and have a direct role in driving intimal hyperplasia and intramural neoangiogenesis. The deficiency of the programmed cell death protein-1 immune checkpoint in GCA, promoting unopposed T cell immunity, contrasts with checkpoint hyperactivity in cancer patients in whom excessive programmed cell death ligand-1 expression paralyzes the function of antitumor T cells. Excessive checkpoint activity is the principle underlying cancer-immune evasion and is therapeutically targeted by immunotherapy with checkpoint inhibitors. Such checkpoint inhibitors, which unleash anticancer T cells and induce immune-related toxicity, may lead to drug-induced vasculitis.

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PD-1/PD-L1 expression profiles within intrahepatic cholangiocarcinoma predict clinical outcome

World Journal of Surgical Oncology ◽

10.1186/s12957-020-02082-5 ◽

2020 ◽

Vol 18 (1) ◽

Author(s):

Lingyu Tian ◽

Jiaqiang Ma ◽

Lijie Ma ◽

Bohao Zheng ◽

Longzi Liu ◽

...

Keyword(s):

T Cells ◽

Cell Death ◽

Programmed Cell Death ◽

Intrahepatic Cholangiocarcinoma ◽

Expression Profiles ◽

Target Therapy ◽

Prognostic Significance ◽

Normal Tissues ◽

Cell Death Protein ◽

Immune Target

Abstract Objective Immunotherapy targeting the programmed cell death protein-1 (PD-1)/programmed cell death protein ligand 1 (PD-L1) pathway has been observed to be efficient in several solid tumors. We aim to investigate the prognostic significance of PD-1/PD-L1 expression profile in intrahepatic cholangiocarcinoma (ICC). Materials and methods We investigated the expression of PD-1, PD-L1, CD8+ T cells, and CD68+ macrophages in paired tumor and adjacent normal tissues from 322 ICC patients using tyramide signal amplification (TSA)-based multiplexed immunohistochemistry. Results We found that high proportion of tumor-infiltrating CD8+ PD-1High within CD8+ PD-1+ T cells significantly correlated with advanced TNM stage (P = 0.035). ICC patients with high proportion of CD8+ PD-1High in CD8+ PD-1+ had worse postoperative survival than low proportion patients (P = 0.0037), which was an independently prognostic factor for OS (P = 0.025,). The density of CD68+ PD-L1+ significantly and positively correlated with the density of CD8+ PD-1High (P < 0.0001, r = 0.5927). The proportion of CD68+ PD-L1+ within CD68+ ICC was the risk factor for OS and TTR but not an independently factor for prognosis. The CD68+ PD-L1+ macrophages and CD8+ PD-1High T cells may cooperatively play a role in inhibiting anti-tumor immunity. Conclusion CD68+ PD-L1+ macrophages and CD8+ PD-1High T cells predict unfavorable prognosis, which could also bring new progress about immune target therapy in ICC research.

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