The Adhesion of Anti-CD3-Activated Mouse T Cells to Syngeneic Colon Adenocarcinoma Cells Is Differentially Regulated by Protein Tyrosine Kinase-, Protein Kinase C-, and cAMP-Dependent Pathways in the Effector Cell

MacKenzie, Willena M.; Blay, Jonathan

doi:10.1006/bbrc.1999.0232

Cited by 5 publications

(3 citation statements)

References 28 publications

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“…Forskolin, cAMP analogs, PDE inhibitors (152, 243–245) and adenosine (188, 246–248) also diminish T cell adherence (152, 243, 246, 248) by down-modulating the expression levels of ICAM-1 (249, 250) as well as of the integrins α 4 (251, 252) and β 2 (251, 253), components of VLA-4 and LFA-1, respectively. Such agents also impair T-cell migration (188, 244, 245, 247) by inducing KCa3.1 inhibition (188, 189).…”

Section: Adenosine-induced Intracellular Camp Accumulation Impairs T mentioning

confidence: 99%

Targeting Adenosine in Cancer Immunotherapy to Enhance T-Cell Function

et al. 2019

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T cells play a critical role in cancer control, but a range of potent immunosuppressive mechanisms can be upregulated in the tumor microenvironment (TME) to abrogate their activity. While various immunotherapies (IMTs) aiming at re-invigorating the T-cell-mediated anti-tumor response, such as immune checkpoint blockade (ICB), and the adoptive cell transfer (ACT) of natural or gene-engineered ex vivo expanded tumor-specific T cells, have led to unprecedented clinical responses, only a small proportion of cancer patients benefit from these treatments. Important research efforts are thus underway to identify biomarkers of response, as well as to develop personalized combinatorial approaches that can target other inhibitory mechanisms at play in the TME. In recent years, adenosinergic signaling has emerged as a powerful immuno-metabolic checkpoint in tumors. Like several other barriers in the TME, such as the PD-1/PDL-1 axis, CTLA-4, and indoleamine 2,3-dioxygenase (IDO-1), adenosine plays important physiologic roles, but has been co-opted by tumors to promote their growth and impair immunity. Several agents counteracting the adenosine axis have been developed, and pre-clinical studies have demonstrated important anti-tumor activity, alone and in combination with other IMTs including ICB and ACT. Here we review the regulation of adenosine levels and mechanisms by which it promotes tumor growth and broadly suppresses protective immunity, with extra focus on the attenuation of T cell function. Finally, we present an overview of promising pre-clinical and clinical approaches being explored for blocking the adenosine axis for enhanced control of solid tumors.

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Section: Adenosine-induced Intracellular Camp Accumulation Impairs T mentioning

confidence: 99%

Targeting Adenosine in Cancer Immunotherapy to Enhance T-Cell Function

et al. 2019

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“…We aimed to compare the effects of HGF, EGF and IGF‐I on PT‐1 cell proliferation and differentiation. As these GFs mediate their biological effects through cell membrane receptors that are functional protein tyrosine kinases [1–3], we further determined the effects of several tyrosine kinase inhibitors (TKI) [23–30].…”

Section: Introductionmentioning

confidence: 99%

Renal proximal tubular cell growth and differentiation are differentially modulated by renotropic growth factors and tyrosine kinase inhibitors

Ernst

Hetzel

Stracke

et al. 2001

Eur J Clin Investigation

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“…The induction of PDE7 seems to be critical for T cell receptor (TCR)-mediated activation (Li et al, 1999). Downstream, cAMP activates a family of cAMP-dependent kinases, the PKA group, although not all cAMP-driven signals are necessarily mediated through PKA (MacKenzie et al, 1999). Despite its ubiquity, signals mediated by cAMP can be cell-specific, even specific for particular locations within a cell (Zaccolo and Pozzan, 2002), because of differences in both cell type-specific expression and subcellular localization of PKA isoforms and their adapters as well as substrates, possibly involving differential interactions with A-kinase anchoring proteins (AKAPs) (Michel and Scott, 2002).…”

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confidence: 99%

Commitment of Activated T Cells to Secondary Responsiveness Is Enhanced by Signals Mediated by cAMP-Dependent Protein Kinase A-I

et al. 2002

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Modalities that induce specific differentiation to T cell memory in immune responses are important for vaccine design, but there is a paucity of well characterized molecular pathways useful to target for this purpose. We have shown previously that pentoxifylline (PF), a phosphodiesterase (PDE) inhibitor in common clinical use, enhances the commitment of in vitro alloprimed human T cells to secondary responsiveness, a characteristic crucial for memory T cells, which are key determinants of the longevity of the immune response. We now show that this effect can also be mediated by activation of adenylate cyclase (AC) and involves PDE4, but not PDE3 or PDE7. PFmediated enhancement of T-cell priming is inhibited by blocking AC, is specifically signaled via cAMP-dependent protein kinase A (PKA) isoform I, and is probably independent of both nuclear factor-B and the mitogen-activated protein kinase cascade. Furthermore, known pharmacological inhibitors of AC or PKA by themselves cannot block T-cell priming in the absence of PF or rolipram (Rm), and enhancement of priming requires the presence of PF only relatively late during a 4-day priming in vitro (at 48 -96 h), suggesting that pharmacological extension of cAMP-mediated signaling can bring about an event critical for T cell commitment to memory. Furthermore, PF and Rm prevent induction of caspase activation and apoptosis in anti-CD3-activated human T cells. Together, our data suggest that PKA-I-mediated signals triggered by prolonging the half-life of cAMP induced during T-cell priming increase survival of activated T cells and enhance memory T cell commitment.To deal effectively with infections in vertebrate hosts, various components of the immune system play important roles. Immunological memory, primarily contributed by T and B lymphocytes, helps significantly toward successful elimination of pathogens during re-exposure. For activation of naive T cells, presentation of peptide-MHC complex by professional antigen presenting cells (APCs) along with accessory signals is necessary (Bernard et al., 2002). Differentiation of antigenexposed T cells into effector phenotypes is crucial for dealing with acute stage of infections, but it also induces death pathways in them, leading to loss of the effector population (Ahmed and Gray, 1996). A residual population of antigentriggered T cells survives as T cell memory and is essential in mediating long-lived immune protection against re-infection ( Swain, 1994;Ahmed and Gray, 1996). The specific pathways leading to effector versus memory T cell differentiation are currently not well understood. Some data support a linear model of differentiation in which all responding T cells become effector T cells, with some surviving as memory (Swain, 1994), whereas other lines of evidence support the possibility that alternate signaling pathways may lead to either effector or memory differentiation (McHeyzer-Williams and Davis, 1995). We have been using a system of in vitro immunization of allo-specific human peripheral T cells by...

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The Adhesion of Anti-CD3-Activated Mouse T Cells to Syngeneic Colon Adenocarcinoma Cells Is Differentially Regulated by Protein Tyrosine Kinase-, Protein Kinase C-, and cAMP-Dependent Pathways in the Effector Cell

Cited by 5 publications

References 28 publications

Targeting Adenosine in Cancer Immunotherapy to Enhance T-Cell Function

Targeting Adenosine in Cancer Immunotherapy to Enhance T-Cell Function

Renal proximal tubular cell growth and differentiation are differentially modulated by renotropic growth factors and tyrosine kinase inhibitors

Commitment of Activated T Cells to Secondary Responsiveness Is Enhanced by Signals Mediated by cAMP-Dependent Protein Kinase A-I

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