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

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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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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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

PLoS ONE ◽

10.1371/journal.pone.0239595 ◽

2020 ◽

Vol 15 (9) ◽

pp. e0239595 ◽

Cited By ~ 1

Author(s):

Amanda Hanson ◽

Kutlu Elpek ◽

Ellen Duong ◽

Lindsey Shallberg ◽

Martin Fan ◽

...

Keyword(s):

T Cell ◽

Tumor Immunity ◽

T Cell Activation ◽

Cell Activation ◽

Cross Linking ◽

Preclinical Models ◽

T Cell Priming

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Expression of Tim-3 drives naïve Treg to an effector-like state with enhanced suppressive activity

10.1101/2020.07.31.230714 ◽

2020 ◽

Author(s):

Hridesh Banerjee ◽

Hector Nieves-Rosado ◽

Aditi Kulkarni ◽

Benjamin Murter ◽

Uma R. Chandran ◽

...

Keyword(s):

T Cell ◽

Tumor Immunity ◽

T Cell Activation ◽

Cell Activation ◽

Suppressive Activity ◽

Tcr Signaling ◽

Self Tolerance ◽

A Cell ◽

Cell Type Specific

AbstractRegulatory T cells (Treg) are critical mediators of self-tolerance but can also limit effective anti-tumor immunity. We and others previously reported that 40-60% percent of Treg-infiltrating head and neck cancer (HNC) and other tumors highly express Tim-3, compared with about 5% in lymphoid organs. Tumor-infiltrating Tim-3+ Treg also have enhanced suppressive function and display a more effector-like phenotype. Using a novel mouse model with cell type-specific Tim-3 expression, we show here that expression of Tim-3 by Treg is sufficient to drive Treg to a more effector-like phenotype, resulting in enhanced suppressive activity and increased tumor growth. These findings may help to reconcile previous reports that some Tim-3 antibodies enhance T cell responses in vivo, while expression of Tim-3 has a cell-intrinsic ability to enhance TCR signaling and T cell activation. Thus, we propose that Tim-3 regulates anti-tumor immunity at least in part through enhancement of Treg function. To our knowledge, this is the first example in which expression of a single co-stimulatory molecule is sufficient to drive differentiation of Treg in this manner.

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ARS2-directed alternative splicing mediates CD28 driven T cell glycolysis and effector function

10.1101/2021.05.07.442963 ◽

2021 ◽

Author(s):

G. Aaron Holling ◽

Anand P Sharda ◽

Mackenzie M Honikel ◽

Caitlin M James ◽

Shivana M Lightman ◽

...

Keyword(s):

T Cells ◽

Alternative Splicing ◽

T Cell ◽

Tumor Immunity ◽

T Cell Activation ◽

Cell Activation ◽

Adaptor Protein ◽

T Cell Survival ◽

And Function ◽

Nascent Transcripts

CD8 T cell activation prompts extensive transcriptome remodeling underlying effector differentiation and function. Regulation of transcriptome composition by the mitogen-inducible nuclear cap-binding complex adaptor protein ARS2 has critical cell type-specific consequences, including thymic T cell survival. Here we show that ARS2 was upregulated by CD28 during activation of peripheral T cells, was essential for anti-tumor immunity, and facilitated T cell activation-induced alternative splicing. The novel splicing function of ARS2 was mediated at least in part by recruitment of splicing factors to nascent transcripts including the M2 isoform of pyruvate kinase (Pkm2), a key determinant of ARS2 function in CD8 T cells. Notably, ARS2-directed Pkm2 splicing occurred days after stimulation of PI3K-indepdendent CD28 signaling and increased glycolysis beyond levels determined by PI3K signaling during T cell priming. Thus, ARS2-directed Pkm2 splicing represents a mechanism by which CD28 drives glycolytic metabolism, allowing for optimal effector cytokine production and T cell anti-tumor immunity.

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