ICOS agonism by JTX-2011 (vopratelimab) requires initial T cell priming and Fc cross-linking for optimal T cell activation and anti-tumor immunity in preclinical models

AbstractThe exploitation of T cell-based immunotherapies and immune checkpoint blockade for cancer treatment has dramatically shifted oncological treatment paradigms and broadened the horizons of cancer immunology. Dendritic cells have emerged as the critical tailors of T cell immune responses, which initiate and coordinate anti-tumor immunity. Importantly, genetic alterations in cancer cells, cytokines and chemokines produced by cancer and stromal cells, and the process of tumor microenvironmental regulation can compromise dendritic cell–T cell cross-talk, thereby disrupting anti-tumor T cell responses. This review summarizes how T cell activation is controlled by dendritic cells and how the tumor microenvironment alters dendritic cell properties in the context of the anti-tumor immune cycle. Furthermore, we will highlight therapeutic options for tailoring dendritic cell-mediated decision-making in T cells for cancer treatment.

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Agonist Anti-Human CD27 Monoclonal Antibody Induces T Cell Activation and Tumor Immunity in Human CD27–Transgenic Mice

The Journal of Immunology ◽

10.4049/jimmunol.1300409 ◽

2013 ◽

Vol 191 (8) ◽

pp. 4174-4183 ◽

Cited By ~ 61

Author(s):

Li-Zhen He ◽

Naseem Prostak ◽

Lawrence J. Thomas ◽

Laura Vitale ◽

Jeffrey Weidlick ◽

...

Keyword(s):

Monoclonal Antibody ◽

T Cell ◽

Transgenic Mice ◽

Tumor Immunity ◽

T Cell Activation ◽

Cell Activation

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T Helper 17 Cells Promote Cytotoxic T Cell Activation in Tumor Immunity

Immunity ◽

10.1016/j.immuni.2009.09.014 ◽

2009 ◽

Vol 31 (5) ◽

pp. 787-798 ◽

Cited By ~ 478

Author(s):

Natalia Martin-Orozco ◽

Pawel Muranski ◽

Yeonseok Chung ◽

Xuexian O. Yang ◽

Tomohide Yamazaki ◽

...

Keyword(s):

T Cell ◽

Tumor Immunity ◽

T Cell Activation ◽

Cell Activation ◽

Cytotoxic T Cell ◽

T Helper ◽

T Helper 17 ◽

T Helper 17 Cells

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Intravenous immunoglobulins suppress T-cell priming by modulating the bidirectional interaction between dendritic cells and natural killer cells

Blood ◽

10.1182/blood-2007-03-077057 ◽

2007 ◽

Vol 110 (9) ◽

pp. 3253-3262 ◽

Cited By ~ 57

Author(s):

Thanyalak Tha-In ◽

Herold J. Metselaar ◽

Hugo W. Tilanus ◽

Zwier M. A. Groothuismink ◽

Ernst J. Kuipers ◽

...

Keyword(s):

Dendritic Cells ◽

T Cell ◽

Nk Cells ◽

T Cell Activation ◽

Cell Activation ◽

Nk Cell ◽

Intravenous Immunoglobulins ◽

Interferon Γ ◽

T Cell Priming ◽

Induced Apoptosis

AbstractThe modes of action of intravenous immunoglobulins (IVIgs) in exerting their immunomodulatory properties are broad and not fully understood. IVIgs can modulate the function of various immune cells, including suppressing the capacity of dendritic cells (DCs) to stimulate T cells. In the present study, we showed that DCs matured in the presence of IVIgs (IVIg-DCs) activated NK cells, and increased their interferon-γ production and degranulation. The activated NK cells induced apoptosis of the majority of IVIg-DCs. In consequence, only in the presence of NK cells, IVIg-DCs were 4-fold impaired in their T-cell priming capacity. This was due to NK-cell–mediated antibody-dependent cellular cytotoxicity (ADCC) to IVIg-DCs, probably induced by IgG multimers, which could be abrogated by blockade of CD16 on NK cells. Furthermore, IVIg-DCs down-regulated the expression of NKp30 and KIR receptors, and induced the generation of CD56brightCD16−CCR7+ lymph node–type NK cells. Our results identify a novel pathway, in which IVIgs induce ADCC of mature DCs by NK cells, which downsizes the antigen-presenting pool and inhibits T-cell priming. By influencing the interaction between DCs and NK cells, IVIgs modulate the ability of the innate immunity to trigger T-cell activation, a mechanism that can “cool down” the immune system at times of activation.

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Dietary methionine restriction impairs anti-tumor immunity through gut microbiota

10.1101/2021.08.27.457955 ◽

2021 ◽

Author(s):

Ming Li ◽

Xiaojiang Xu ◽

Qing Xu ◽

Xin Xu ◽

M Andrea Azcarate-Peril ◽

...

Keyword(s):

Hydrogen Sulfide ◽

Immune System ◽

T Cell ◽

Gut Microbiota ◽

Tumor Growth ◽

Tumor Immunity ◽

T Cell Activation ◽

Cell Activation ◽

Cancer Growth ◽

Methionine Restriction

Dietary methionine restriction has been reported to repress cancer growth and improve therapeutic responses in several pre-clinical settings. However, how this dietary intervention impacts cancer progression in the context of the intact immune system is unknown. Here we report that methionine restriction exacerbates cancer growth and influences the outcomes of anti-tumor immunotherapy through gut microbiota and immune suppression in immunocompetent settings. Methionine restriction reduces T cell activation, increases tumor growth, and impairs response to anti-tumor immunotherapy. Mechanistically, methionine restriction alters composition of gut microbiota and reduces microbial production of hydrogen sulfide. Fecal transplantation from methionine-restricted tumor-free animals is sufficient to repress T cell activation and enhance tumor growth in tumor-bearing recipient mice. Conversely, dietary supplementation of a hydrogen sulfide donor or methionine stimulates anti-tumor immunity and suppresses tumor progression. Our findings reveal a vital role of gut microbiota in mediating methionine restriction-induced suppression of anti-tumor immunity and suggest that any possible anti-cancer benefits of methionine restriction require careful considerations of both the microbiota and the immune system.

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Alterations in tyrosine protein phosphorylation induced by antibody-mediated cross-linking of the CD4 receptor of T lymphocytes

Molecular and Cellular Biology ◽

10.1128/mcb.9.10.4441-4446.1989 ◽

1989 ◽

Vol 9 (10) ◽

pp. 4441-4446

Author(s):

A Veillette ◽

J B Bolen ◽

M A Bookman

Keyword(s):

T Cell ◽

Protein Phosphorylation ◽

T Cell Activation ◽

Cell Activation ◽

Cross Linking ◽

Rapid Changes ◽

Tyrosine Protein Kinase ◽

Enzymatic Activation ◽

Intracellular Signal ◽

Carboxy Terminal

Accumulating data suggest that the CD4 T-cell surface antigen transduces an independent intracellular signal during antigen-mediated T-cell activation. CD4 is physically associated with the internal membrane tyrosine protein kinase p56lck and can mediate, after antibody-mediated cross-linking, the rapid enzymatic activation of Lck, implying that CD4 signalling may involve changes in tyrosine protein phosphorylation. In this report, we describe that cross-linking of CD4 results in a series of rapid changes in intracellular tyrosine protein phosphorylation. The most prominent CD4-induced tyrosine phosphorylation change involved p56lck, which became extensively phosphorylated on the carboxy-terminal tyrosine residue 505 and, to a lesser extent, lymphocytes can transduce an intracellular signal resulting in tyrosine protein phosphorylation and strongly suggest that this property of CD4 is mediated through p56lck.

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Abstract 4845: HERA-CD27L, a true CD27 agonist, is a hexavalent CD27 ligand that enhances T cell activation and induces potent anti-tumor immunity

10.1158/1538-7445.sabcs18-4845 ◽

2019 ◽

Author(s):

Julian P. Sefrin ◽

David M. Richards ◽

Katharina Billian-Frey ◽

Karl Heinonen ◽

Viola Marschall ◽

...

Keyword(s):

T Cell ◽

Tumor Immunity ◽

T Cell Activation ◽

Cell Activation

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Targeting of T lymphocytes against egf-receptor+ tumor cells by bispecific monoclonal antibodies: Requirement of CD3 molecule cross-linking for t-cell activation

International Journal of Cancer ◽

10.1002/ijc.2910550610 ◽

1993 ◽

Vol 55 (6) ◽

pp. 931-937 ◽

Cited By ~ 12

Author(s):

Silvano Ferrini ◽

Anna Cambiaggi ◽

Sabrina Sforzini ◽

Sabrina Marciano ◽

Silvana Canevari ◽

...

Keyword(s):

Monoclonal Antibodies ◽

T Cell ◽

T Lymphocytes ◽

Tumor Cells ◽

T Cell Activation ◽

Cell Activation ◽

Egf Receptor ◽

Cross Linking

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Evidence for differential intracellular signaling via CD4 and CD8 molecules.

Journal of Experimental Medicine ◽

10.1084/jem.179.2.727 ◽

1994 ◽

Vol 179 (2) ◽

pp. 727-732 ◽

Cited By ~ 41

Author(s):

K S Ravichandran ◽

S J Burakoff

Keyword(s):

Protein Kinase C ◽

T Cell ◽

Protein Kinase ◽

T Cell Activation ◽

Intracellular Signaling ◽

Cell Activation ◽

Interleukin 2 ◽

Kinase Assay ◽

Cross Linking ◽

Kinase C

Although both the CD4 and CD8 molecules enhance antigen responsiveness mediated by the T cell receptor (TCR), it is not known whether CD4 and CD8 initiate similar or different intracellular signals when they act as coreceptors. To characterize the early signals transmitted by CD4 and CD8, both CD4 and CD8 alpha were expressed in the same murine T cell hybridoma. In the double positive transfectants, CD4 and CD8 associated with equal amounts of p56lck (Lck), and both molecules enhanced interleukin 2 (IL-2) production equivalently when cross-linked with suboptimal levels of anti-TCR antibody. However, in an in vitro kinase assay, cross-linking CD4 initiated fourfold greater kinase activity compared with CD8 cross-linking. In the same assay, when CD4 or CD8 was cross-linked to the TCR, novel phosphorylated proteins were found associated with the TCR/CD4 complex but not with the TCR/CD8 complex. Consistent with this data, antiphosphotyrosine immunoblotting revealed greater tyrosine phosphorylation of intracellular substrates after TCR/CD4 cross-linking compared with TCR/CD8 cross-linking. Additionally, a specific protein kinase C inhibitor (RO318220) inhibited CD8-mediated enhancement of IL-2 production far more effectively than CD4-mediated enhancement. Thus, it appears that CD8 alpha may depend more on a protein kinase C-mediated signaling pathway, whereas CD4 may rely on greater tyrosine kinase activation. Such differential signaling via CD4 and CD8 has implications for thymic ontogeny and T cell activation.

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