Update on the Current Revolution in Cancer Immunotherapy

Renrick, Ariana N.; Dunbar, Zerick Terrell; Shanker, Anil

doi:10.2217/imt-2018-0135

Cited by 12 publications

(12 citation statements)

References 20 publications

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“…However, no direct data are yet available to show the efficacy of such Notch ligand constructs to human cancers. Nevertheless, the consensus is building that regulation of Notch in cancer immunity is a very attractive approach [42] that will further enhance therapeutic success in the ongoing revolution in cancer immunotherapy [43, 44]. Thus, strategies incorporating selectively engineered Notch ligands could open a new approach of therapeutics for modulating immunity in various immunosuppressive conditions including cancer.…”

Section: Discussionmentioning

confidence: 99%

Determinant roles of dendritic cell-expressed Notch Delta-like and Jagged ligands on anti-tumor T cell immunity

Tchekneva

Goruganthu

Uzhachenko

et al. 2019

j. immunotherapy cancer

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Background Notch intercellular communication instructs tissue-specific T-cell development and function. In this study, we explored the roles of dendritic cell (DC)-expressed Notch ligands in the regulation of T-cell effector function. Methods We generated mice with CD11c lineage-specific deletion of Notch Delta-like ligand (Dll)1 and Jagged (Jag)2. Using these genetically-ablated mice and engineered pharmacological Notch ligand constructs, the roles of various Delta-like and Jagged ligands in the regulation of T-cell-mediated immunity were investigated. We assessed tumor growth, mouse survival, cytokine production, immunophenotyping of myeloid and lymphoid populations infiltrating the tumors, expression of checkpoint molecules and T-cell function in the experimental settings of murine lung and pancreatic tumors and cardiac allograft rejection. Correlative studies were also performed for the expression of NOTCH ligands, NOTCH receptors and PD-1 on various subsets of myeloid and lymphoid cells in tumor-infiltrating immune cells analyzed from primary human lung cancers. Results Mice with CD11c lineage-specific deletion of Notch ligand gene Dll1 , but not Jag2 , exhibited accelerated growth of lung and pancreatic tumors concomitant with decreased antigen-specific CD8 + T-cell functions and effector-memory (Tem) differentiation. Increased IL-4 but decreased IFN-γ production and elevated populations of T-regulatory and myeloid-derived suppressor cells were observed in Dll1 -ablated mice. Multivalent clustered DLL1-triggered Notch signaling overcame DC Dll1 deficiency and improved anti-tumor T-cell responses, whereas the pharmacological interference by monomeric soluble DLL1 construct suppressed the rejection of mouse tumors and cardiac allograft. Moreover, monomeric soluble JAG1 treatment reduced T-regulatory cells and improved anti-tumor immune responses by decreasing the expression of PD-1 on CD8 + Tem cells. A significant correlation was observed between DC-expressed Jagged and Delta-like ligands with Tem-expressed PD-1 and Notch receptors, respectively, in human lung tumor-infiltrates. Conclusion Our data show the importance of specific expression of Notch ligands on DCs in the regulation of T-cell effector function. Thus, strategies incorporating selectively engineered Notch ligands could provide a novel approach of therapeutics for modulating immunity in various immunosuppressive conditions including cancer. Electronic supplementary material The online version of this article (10.1186/s40425-019-0566-4) contains supplementary material, which is available to authorized users.

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Section: Discussionmentioning

confidence: 99%

Determinant roles of dendritic cell-expressed Notch Delta-like and Jagged ligands on anti-tumor T cell immunity

Tchekneva

Goruganthu

Uzhachenko

et al. 2019

j. immunotherapy cancer

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“…T lymphocytes are potent weapons used to control the emergence and growth of tumors. Despite tremendous progress in our understanding of T cell biology and unprecedented success in harnessing antitumor immunity to treat cancer, 1 there remains a challenge to unleash the full power of T lymphocytes to attack tumors. Immunotherapeutic strategies, such as the use of adoptive cellular therapies and biologics, are ineffective in a significant proportion of cancer patients.…”

Section: Introductionmentioning

confidence: 99%

Extracellular K⁺Dampens T Cell Functions: Implications for Immune Suppression in the Tumor Microenvironment

Ong

et al. 2019

Bioelectricity

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Background: Dying tumor cells release intracellular potassium (K +), raising extracellular K + ([K + ] e) in the tumor microenvironment (TME) to 40-50 mM (high-[K + ] e). Here, we investigated the effect of high-[K + ] e on T cell functions. Materials and Methods: Functional impacts of high-[K + ] e on human T cells were determined by cellular, molecular, and imaging assays. Results: Exposure to high-[K + ] e suppressed the proliferation of central memory and effector memory T cells, while T memory stem cells were unaffected. High-[K + ] e inhibited T cell cytokine production and dampened antitumor cytotoxicity, by modulating the Akt signaling pathway. High-[K + ] e caused significant upregulation of the immune checkpoint protein PD-1 in activated T cells. Although the number of K Ca 3.1 calcium-activated potassium channels expressed in T cells remained unaffected under high-[K + ] e , a novel K Ca 3.1 activator, SKA-346, rescued T cells from high-[K + ] e-mediated suppression. Conclusion: High-[K + ] e represents a so far overlooked secondary checkpoint in cancer. K Ca 3.1 activators could overcome such ''ionic-checkpoint''-mediated immunosuppression in the TME, and be administered together with known PD-1 inhibitors and other cancer therapeutics to improve outcomes.

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“…The neuroimmune approaches could be harnessed to improve antitumor responses in metastatic cancers where we are far from achieving the goal of preventive or therapeutic modality assuring relapse-free survival (287). Tumor cells show chemotaxis toward neurotransmitters such as DA and other catecholamines (288).…”

Section: Therapeutic Potential Of Neuroimmune Modulationmentioning

confidence: 99%

Critical Neurotransmitters in the Neuroimmune Network

et al. 2020

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Immune cells rely on cell-cell communication to specify and fine-tune their responses. They express an extensive network of cell communication modes, including a vast repertoire of cell surface and transmembrane receptors and ligands, membrane vesicles, junctions, ligand and voltage-gated ion channels, and transporters. During a crosstalk between the nervous system and the immune system these modes of cellular communication and the downstream signal transduction events are influenced by neurotransmitters present in the local tissue environments in an autocrine or paracrine fashion. Neurotransmitters thus influence innate and adaptive immune responses. In addition, immune cells send signals to the brain through cytokines, and are present in the brain to influence neural responses. Altered communication between the nervous and immune systems is emerging as a common feature in neurodegenerative and immunopathological diseases. Here, we present the mechanistic frameworks of immunostimulatory and immunosuppressive effects critical neurotransmitters-dopamine (3,4-dihydroxyphenethylamine), serotonin (5hydroxytryptamine), substance P (trifluoroacetate salt powder), and L-glutamateexert on lymphocytes and non-lymphoid immune cells. Furthermore, we discuss the possible roles neurotransmitter-driven neuroimmune networks play in the pathogenesis of neurodegenerative disorders, autoimmune diseases, cancer, and outline potential clinical implications of balancing neuroimmune crosstalk by therapeutic modulation.

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Update on the Current Revolution in Cancer Immunotherapy

Cited by 12 publications

References 20 publications

Determinant roles of dendritic cell-expressed Notch Delta-like and Jagged ligands on anti-tumor T cell immunity

Determinant roles of dendritic cell-expressed Notch Delta-like and Jagged ligands on anti-tumor T cell immunity

Extracellular K⁺Dampens T Cell Functions: Implications for Immune Suppression in the Tumor Microenvironment

Critical Neurotransmitters in the Neuroimmune Network

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Update on the Current Revolution in Cancer Immunotherapy

Cited by 12 publications

References 20 publications

Determinant roles of dendritic cell-expressed Notch Delta-like and Jagged ligands on anti-tumor T cell immunity

Determinant roles of dendritic cell-expressed Notch Delta-like and Jagged ligands on anti-tumor T cell immunity

Extracellular K+Dampens T Cell Functions: Implications for Immune Suppression in the Tumor Microenvironment

Critical Neurotransmitters in the Neuroimmune Network

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Product

Resources

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Extracellular K⁺Dampens T Cell Functions: Implications for Immune Suppression in the Tumor Microenvironment