Identification of a monoclonal antibody that targets PD-1 in a manner requiring PD-1 Asn58 glycosylation

Abstract Programmed cell death 1 (PD-1) is inhibitory receptor and immune checkpoint protein. Blocking the interaction of PD-1 and its ligands PD-L1/ L2 is able to active T-cell-mediated antitumor response. Monoclonal antibody-based drugs targeting PD-1 pathway have exhibited great promise in cancer therapy. Here we show that MW11-h317, an anti-PD-1 monoclonal antibody, displays high affinity for PD-1 and blocks PD-1 interactions with PD-L1/L2. MW11-h317 can effectively induce T-cell-mediated immune response and inhibit tumor growth in mouse model. Crystal structure of PD-1/MW11-h317 Fab complex reveals that both the loops and glycosylation of PD-1 are involved in recognition and binding, in which Asn58 glycosylation plays a critical role. The unique glycan epitope in PD-1 to MW11-h317 is different from the first two approved clinical PD-1 antibodies, nivolumab and pembrolizumab. These results suggest MW11-h317 as a therapeutic monoclonal antibody of PD-1 glycosylation-targeting which may become efficient alternative for cancer therapy.

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WNT-1 Signaling Inhibits Apoptosis by Activating β-Catenin/T Cell Factor–Mediated Transcription

The Journal of Cell Biology ◽

10.1083/jcb.152.1.87 ◽

2001 ◽

Vol 152 (1) ◽

pp. 87-96 ◽

Cited By ~ 263

Author(s):

Shaoqiong Chen ◽

Denis C. Guttridge ◽

Zongbing You ◽

Zhaochen Zhang ◽

Andrew Fribley ◽

...

Keyword(s):

T Cell ◽

Cancer Therapy ◽

Wnt Signaling ◽

Cell Survival ◽

Critical Role ◽

Survival Function ◽

Dominant Negative ◽

Dominant Negative Mutant ◽

Cytochrome C Release ◽

T Cell Factor

Wnt signaling plays a critical role in development and oncogenesis. Although significant progress has been made in understanding the downstream signaling cascade of Wnt signaling, little is known regarding Wnt signaling modification of the cell death machinery. Given that numerous oncogenes transform cells by providing cell survival function, we hypothesized that Wnt signaling may inhibit apoptosis. Here, we report that cells expressing Wnt-1 were resistant to cancer therapy–mediated apoptosis. Wnt-1 signaling inhibited the cytochrome c release and the subsequent caspase-9 activation induced by chemotherapeutic drugs, including both vincristine and vinblastine. Furthermore, we found that Wnt-1–mediated cell survival was dependent on the activation of β-catenin/T cell factor (Tcf) transcription. Inhibition of β-catenin/Tcf transcription by expression of the dominant-negative mutant of Tcf-4 blocked Wnt-1–mediated cell survival and rendered cells sensitive to apoptotic stimuli. These results provide the first demonstration that Wnt-1 inhibits cancer therapy–mediated apoptosis and suggests that Wnt-1 may exhibit its oncogenic potential through a mechanism of anti-apoptosis.

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Targeting OX40 by monoclonal antibody PF-04518600 to enhance T cell functions and inhibit tumor growth.

Journal of Clinical Oncology ◽

10.1200/jco.2016.34.15_suppl.e14518 ◽

2016 ◽

Vol 34 (15_suppl) ◽

pp. e14518-e14518

Author(s):

Hua Long ◽

Ann L White ◽

Brittany B Jiang ◽

Reid Feldman ◽

Danielle C Pappas ◽

...

Keyword(s):

Monoclonal Antibody ◽

T Cell ◽

Tumor Growth ◽

Inhibit Tumor Growth ◽

Cell Functions

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Newly emerged immunogenic neoantigens in established tumors enable hosts to regain immunosurveillance in a T-cell-dependent manner

International Immunology ◽

10.1093/intimm/dxaa049 ◽

2020 ◽

Vol 33 (1) ◽

pp. 39-48

Author(s):

Tomoaki Muramatsu ◽

Takuro Noguchi ◽

Daisuke Sugiyama ◽

Yoshie Kanada ◽

Kaori Fujimaki ◽

...

Keyword(s):

T Cells ◽

T Cell ◽

Tumor Growth ◽

Cd8 T Cells ◽

Immune Escape ◽

Critical Role ◽

Genetic Alterations ◽

Dependent Manner ◽

Inhibit Tumor Growth ◽

Immune Escape Mechanisms

Abstract Tumor neoantigens derived from genetic alterations are potential T-cell targets for antitumor immunity. However, tumors develop immune escape mechanisms including loss of preexisting neoantigens and/or impairment of T-cell responses during tumor development and progression. Here, we addressed whether newly emerged immunogenic neoantigens in established tumors enabled hosts to inhibit tumor growth via controlling immune escape mechanisms. Using a doxycycline-driven gene expression system, we generated murine MC38, CT26 (colorectal cancer) and B16 (melanoma) cell lines with inducible expression of model immunogenic neoantigens such as chicken ovalbumin and human NY-ESO-1. A model neoantigen was induced by doxycycline administration in the tumors once tumors became palpable. Tumor growth was significantly inhibited upon induction of the neoantigen and this inhibition was abrogated in nude mice lacking T cells and in mice deprived of CD8+ T cells, indicating the critical role of CD8+ T cells in tumor regression. In addition, PD-1/PD-L1 blockade further augmented the antitumor immune response, resulting in a far stronger inhibition of tumor growth. Accordingly, newly emerged tumor neoantigen-specific CD8+ T cells with enhanced effector functions were significantly increased in mice treated with PD-1/PD-L1 blockade. We propose that a newly emerged neoantigen is sufficient to inhibit tumor growth via preventing immune escape in a T-cell-dependent manner. Our results imply that induction of immunogenic tumor neoantigens is a novel strategy to overcome the resistance to immune checkpoint blockade therapy.

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Role of Myeloid Cells in Oncolytic Reovirus-Based Cancer Therapy

Viruses ◽

10.3390/v13040654 ◽

2021 ◽

Vol 13 (4) ◽

pp. 654

Author(s):

Vishnupriyan Kumar ◽

Michael A. Giacomantonio ◽

Shashi Gujar

Keyword(s):

T Cell ◽

Cancer Therapy ◽

Critical Role ◽

Myeloid Cells ◽

Myeloid Cell ◽

Antitumor Effects ◽

Cell Responses ◽

Combination Strategies ◽

Cell Immunity

Oncolytic reovirus preferentially targets and kills cancer cells via the process of oncolysis, and additionally drives clinically favorable antitumor T cell responses that form protective immunological memory against cancer relapse. This two-prong attack by reovirus on cancers constitutes the foundation of its use as an anticancer oncolytic agent. Unfortunately, the efficacy of these reovirus-driven antitumor effects is influenced by the highly suppressive tumor microenvironment (TME). In particular, the myeloid cell populations (e.g., myeloid-derived suppressive cells and tumor-associated macrophages) of highly immunosuppressive capacities within the TME not only affect oncolysis but also actively impair the functioning of reovirus-driven antitumor T cell immunity. Thus, myeloid cells within the TME play a critical role during the virotherapy, which, if properly understood, can identify novel therapeutic combination strategies potentiating the therapeutic efficacy of reovirus-based cancer therapy.

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