T cell receptor activation status as biological context for interpreting PD1/PDL1 biomarker measurements.

2018 ◽  
Vol 36 (5_suppl) ◽  
pp. 54-54
Author(s):  
Ralph E. Parchment ◽  
Tony Navas ◽  
Kristin Fino ◽  
Andy Fung ◽  
Facundo Cutuli ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
T Cell Receptor ◽  
Tumor Immunity ◽  
Cd8 T Cells ◽  
Immune Checkpoint ◽  
Immunofluorescence Microscopy ◽  
Cell Receptor ◽  
Receptor Activation ◽  
Tcr Activation

54 Background: Direct cytolysis of tumor cells by CD8+ T cells results from the net effect of at least two biochemical pathways: (1) stimulatory signaling from the activated T cell receptor (TCR) complex in response to its recognition of a tumor neoantigen presented in the context of autologous MHC class I, and (2) suppressive signaling from immune checkpoints, such as the response of PD1 to binding its ligand, PDL1. Because the PD1:PDL1 immune checkpoint is significant for therapy only when there is tumor cell-specific TCR activation and signaling, it is not surprising that simple measurements of either PD1 or PDL1 in tumor biopsies are, at best, imperfect predictive biomarkers. Instead, a more precise test that quantifies PD1 signaling due to PDL1 binding only in the subset of CD8+ T cells exhibiting activated TCR signaling should provide a more accurate assessment of the extent of immune checkpoint suppression of tumor immunity and therefore be a more predictive biomarker of response to PD1/PDL1-targeted immunotherapy. Methods: We have developed a multiplexed immunofluorescence microscopy test capable of simultaneous quantitation of TCR activation (phospho-CD3zeta), immune checkpoint signaling via PD1 (phospho-SHP1 and -SHP2), and the net stimulation or inhibition resulting from the integration of these two pathways (phospho-ZAP70). Results: Specific antibodies to these biomarkers have been qualified, including peptide inhibition studies to establish antibody specificity, and their performance established by fit-for-purpose studies of in vitro models of CD8+ T cell activation. This multiplex biomarker panel is suitable for clinical use with formalin-fixed, paraffin embedded core needle biopsies of tumor and quantitative immunofluorescence microscopy (qIFA). Conclusions: The additional biomarkers of tumor immunity are expected to add an important context for interpreting PD1/PDL1 measurements. Funded by NCI Contract No. HHSN261200800001E.

scholarly journals CD8+T Cells in HIV Disease Exhibit Cytokine Receptor Perturbation and Poor T Cell Receptor Activation but Are Responsive to γ‐Chain Cytokine–Driven Proliferation

2006 ◽  
Vol 193 (6) ◽  
pp. 879-887 ◽  
Author(s):  
Rajendra Pahwa ◽  
Thomas W. McCloskey ◽  
Olga C. Aroniadis ◽  
Natasa Strbo ◽  
Subramaniam Krishnan ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
T Cell Receptor ◽  
Cd8 T Cells ◽  
Cell Receptor ◽  
Receptor Activation ◽  
Cytokine Receptor ◽  
Hiv Disease

KLRG1 signaling induces defective Akt (ser473) phosphorylation and proliferative dysfunction of highly differentiated CD8+ T cells

Blood ◽  
2009 ◽  
Vol 113 (26) ◽  
pp. 6619-6628 ◽  
Author(s):  
Sian M. Henson ◽  
Ornella Franzese ◽  
Richard Macaulay ◽  
Valentina Libri ◽  
Rita I. Azevedo ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
T Cell Receptor ◽  
Cd8 T Cells ◽  
Replicative Senescence ◽  
Cell Receptor ◽  
Telomerase Activity ◽  
Receptor Activation ◽  
Inhibitory Receptor ◽  
Functional Changes

Abstract Highly differentiated CD8+CD28−CD27− T cells have short telomeres, defective telomerase activity, and reduced capacity for proliferation, indicating that they are close to replicative senescence. In addition, these cells express increased levels of the senescence-associated inhibitory receptor KLRG1 and have poor capacity for IL-2 synthesis and defective Akt (ser473) phosphorylation after activation. It is not known whether signaling via KLRG1 contributes to any of the attenuated differentiation-related functional changes in CD8+ T cells. To address this, we blocked KLRG1 signaling during T-cell receptor activation using antibodies against its major ligand, E-cadherin. This resulted in a significant enhancement of Akt (ser473) phosphorylation and T-cell receptor–induced proliferative activity of CD8+CD28−CD27− T cells. Furthermore, the increase of proliferation was directly linked to the Akt-mediated induction of cyclin D and E and reduction in the cyclin inhibitor p27 expression. In contrast, the reduced telomerase activity in highly differentiated CD8+CD28−CD27− T cells was not altered by KLRG1 blockade, indicating the involvement of other mechanisms. This is the first demonstration of a functional role for KLRG1 in primary human CD8+ T cells and highlights that certain functional defects that arise during progressive T-cell differentiation toward replicative senescence are maintained actively by inhibitory receptor signaling.

scholarly journals Inhibition of T Cell Receptor Activation by Semi-Synthetic Sesquiterpene Lactone Derivatives and Molecular Modeling of Their Interaction with Glutathione and Tyrosine Kinase ZAP-70

Molecules ◽  
2019 ◽  
Vol 24 (2) ◽  
pp. 350 ◽  
Author(s):  
Andrei Khlebnikov ◽  
Igor Schepetkin ◽  
Anarkul Kishkentaeva ◽  
Zhanar Shaimerdenova ◽  
Gayane Atazhanova ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Tyrosine Kinase ◽  
T Cell Receptor ◽  
Sesquiterpene Lactones ◽  
Cell Receptor ◽  
Receptor Activation ◽  
Tcr Signaling ◽  
Jurkat T Cells ◽  
Tcr Activation

A variety of natural compounds have been shown to modulate T cell receptor (TCR) activation, including natural sesquiterpene lactones (SLs). In the present studies, we evaluated the biological activity of 11 novel semi-synthetic SLs to determine their ability to modulate TCR activation. Of these compounds, α -epoxyarglabin, cytisinyl epoxyarglabin, 1 β ,10 α -epoxyargolide, and chloroacetate grosheimin inhibited anti-CD3-induced Ca2+ mobilization and extracellular signal-regulated kinase 1/2 (ERK1/2) phosphorylation in Jurkat T cells. We also found that the active SLs depleted intracellular glutathione (GSH) in Jurkat T cells, supporting their reactivity towards thiol groups. Because the zeta-chain associated tyrosine kinase 70 kDa (ZAP-70) is essential for TCR signaling and contains a tandem SH2 region that is highly enriched with multiple cysteines, we performed molecular docking of natural SLs and their semi-synthetic derivatives into the ZAP-70 binding site. The docking showed that the distance between the carbon atom of the exocyclic methylene group and the sulfur atom in Cys39 of the ZAP-70 tandem SH2 module was 3.04–5.3 Å for active compounds. Furthermore, the natural SLs and their derivatives could be differentiated by their ability to react with the Cys39 SH-group. We suggest that natural and/or semi-synthetic SLs with an α -methylene- γ -lactone moiety can specifically target GSH and the kinase site of ZAP-70 and inhibit the initial phases of TCR activation.

scholarly journals Bcl-2 differentially regulates Ca2+ signals according to the strength of T cell receptor activation

2006 ◽  
Vol 172 (1) ◽  
pp. 127-137 ◽  
Author(s):  
Fei Zhong ◽  
Michael C. Davis ◽  
Karen S. McColl ◽  
Clark W. Distelhorst
Keyword(s):  
T Cells ◽  
T Cell ◽  
T Cell Receptor ◽  
Cell Receptor ◽  
Receptor Activation ◽  
Receptor Subtypes ◽  
Activated T Cells ◽  
High Concentrations ◽  
Tcr Activation ◽  
Insp3 Receptor

To investigate the effect of Bcl-2 on Ca2+ signaling in T cells, we continuously monitored Ca2+ concentration in Bcl-2–positive and –negative clones of the WEHI7.2 T cell line after T cell receptor (TCR) activation by anti-CD3 antibody. In Bcl-2–negative cells, high concentrations of anti-CD3 antibody induced a transient Ca2+ elevation, triggering apoptosis. In contrast, low concentrations of anti-CD3 antibody induced Ca2+ oscillations, activating the nuclear factor of activated T cells (NFAT), a prosurvival transcription factor. Bcl-2 blocked the transient Ca2+ elevation induced by high anti-CD3, thereby inhibiting apoptosis, but did not inhibit Ca2+ oscillations and NFAT activation induced by low anti-CD3. Reduction in the level of all three inositol 1,4,5-trisphosphate (InsP3) receptor subtypes by small interfering RNA inhibited the Ca2+ elevation induced by high but not low anti-CD3, suggesting that Ca2+ responses to high and low anti-CD3 may have different requirements for the InsP3 receptor. Therefore, Bcl-2 selectively inhibits proapoptotic Ca2+ elevation induced by strong TCR activation without hindering prosurvival Ca2+ signals induced by weak TCR activation.

scholarly journals Control of HIV-1 immune escape by CD8 T cells expressing enhanced T-cell receptor

2008 ◽  
Vol 14 (12) ◽  
pp. 1390-1395 ◽  
Author(s):  
Angel Varela-Rohena ◽  
Peter E Molloy ◽  
Steven M Dunn ◽  
Yi Li ◽  
Megan M Suhoski ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
T Cell Receptor ◽  
Cd8 T Cells ◽  
Immune Escape ◽  
Cell Receptor ◽  
Hiv 1
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