Correlation between local 18F-fluorodeoxyglucose PET/CT and T cell exhaustion for predicting treatment response in patients with advanced melanoma treated with checkpoint inhibitor mono-therapy.

2016 ◽  
Vol 34 (15_suppl) ◽  
pp. 11572-11572
Author(s):  
Miguel Hernandez Pampaloni ◽  
Lorenzo Nardo ◽  
Alain Patrick Algazi ◽  
Katy K. Tsai ◽  
Kimberly Loo ◽  
...  
Keyword(s):  
T Cell ◽  
Treatment Response ◽  
Checkpoint Inhibitor ◽  
Advanced Melanoma ◽  
T Cell Exhaustion ◽  
Cell Exhaustion ◽  
18F Fluorodeoxyglucose ◽  
Pet Ct ◽  
Fluorodeoxyglucose Pet

scholarly journals 251 The use of small molecule inhibitors to target novel pathways in exhausted T cells for immuno-oncology therapeutic intervention

2021 ◽  
Vol 9 (Suppl 3) ◽  
pp. A271-A271
Author(s):  
Francis Acklam ◽  
Joanne Hay ◽  
Darryl Turner ◽  
Mark Barbour ◽  
Preeti Singh ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Small Molecule ◽  
Therapeutic Intervention ◽  
Checkpoint Inhibitor ◽  
Great Promise ◽  
Cell Phenotype ◽  
T Cell Exhaustion ◽  
Cell Exhaustion

BackgroundThe ability to reverse exhaustion in CD8+ T cells holds great promise for therapeutic intervention in oncology. Indeed, treatment with therapeutics targeted at checkpoint inhibitors, such as Nivolumab (anti-PD-1), have shown great promise in the treatment of a subset of individuals and tumour types. However, pre-clinical success does not always translate to success in clinical trials and resistance to these approaches is prevalent. As such, there is a pressing need to develop novel approaches that target alternative pathways for use alone or potentially in combination with checkpoint inhibitor modulation. A secondary need is the requirement for advanced assays that accurately recapitulate the pathways and cell phenotypes prevalent in the tumour environment.MethodsHere we describe the characteristics of an in vitro human T cell exhaustion assay whereby in vitro stimulated T cells phenotypically and functionally recapitulate the exhausted T cells found within the tumour microenvironment. We also demonstrate the effect of checkpoint blockade as well as small molecule inhibition of a novel target on the exhausted T cell phenotype.ResultsIn this assay, exhaustion can be partially but not fully reversed by treatment with anti-PD-1 alone. In addition, we demonstrate the effect of a small molecule inhibitor targeting IKZF3, a transcription factor shown to be upregulated in T cell exhaustion, on reversing T cell exhaustion alone and in combination with checkpoint inhibitor blockade.ConclusionsThese assays and approaches enable investigation into the ability of compounds to influence reversal of T cell exhaustion where anti-PD-1 treatment does not fully reverse the exhausted phenotype and offers the ability to test combination therapy approaches.AcknowledgementsThis work was aided by the valuable input and insight of Professor Stephen Anderton.Ethics ApprovalThe study obtained ethics approval from West Midlands – Black Country Research Ethics Committee under IRAS project ID 270936. All donors gave informed consent before taking part.

scholarly journals Checkpoint inhibitor blockade and epigenetic reprogrammability in CD8+ T-cell activation and exhaustion

2020 ◽  
Vol 8 ◽  
pp. 251513552090423
Author(s):  
José Belizário ◽  
Maria Fernanda Destro Rodrigues
Keyword(s):  
T Cell ◽  
T Cell Activation ◽  
Dna Methyltransferase ◽  
Cell Activation ◽  
Checkpoint Inhibitor ◽  
Simian Virus 40 ◽  
Simian Virus ◽  
T Antigen ◽  
T Cell Exhaustion ◽  
Cell Exhaustion

CD8+ T-cell exhaustion is a dysfunctional state that is regulated through the expression of inhibitory checkpoint receptor genes including the cytotoxic T-lymphocyte–associated antigen 4, programmed death 1, and DNA methylation of effector genes interferon-γ, perforin, and granzyme B. Different strategies have been used to reverse T-cell exhaustion, which is an adverse event of checkpoint inhibitor blockade. Here, we present the mechanisms by which DNA methyltransferase inhibitors and Simian virus 40 large T antigen through viral mimicry can promote the reversion of exhausted CD8+ T cells. We examine how these pharmacological strategies can work together to improve the clinical efficacy of immunotherapies.

scholarly journals Exploring Markers of Exhausted CD8 T Cells to Predict Response to Immune Checkpoint Inhibitor Therapy for Hepatocellular Carcinoma

Liver Cancer ◽  
2021 ◽  
pp. 1-14
Author(s):  
Chia-Lang Hsu ◽  
Da-Liang Ou ◽  
Li-Yuan Bai ◽  
Chia-Wei Chen ◽  
Li Lin ◽  
...  
Keyword(s):  
Hepatocellular Carcinoma ◽  
T Cell ◽  
Tumor Microenvironment ◽  
Immune Checkpoint ◽  
Immune Checkpoint Inhibitor ◽  
Checkpoint Inhibitor ◽  
Cd8 T Cell ◽  
Gene Signature ◽  
T Cell Exhaustion ◽  
Cell Exhaustion

<b><i>Background:</i></b> Reversal of CD8 T-cell exhaustion was considered a major antitumor mechanism of anti-programmed cell death-1 (PD-1)/ anti-programmed death ligand-1 (PD-L1)-based immune checkpoint inhibitor (ICI) therapy. <b><i>Objectives:</i></b> The aim of this study was to identify markers of T-cell exhaustion that is best associated with ICI treatment efficacy for advanced hepatocellular carcinoma (HCC). <b><i>Methods:</i></b> Immune cell composition of archival tumor samples was analyzed by transcriptomic analysis and multiplex immunofluorescence staining. <b><i>Results:</i></b> HCC patients with objective response after anti-PD-1/anti-PD-L1-based ICI therapy (<i>n</i> = 42) had higher expression of genes related to T-cell exhaustion. A 9-gene signature (LAG3, CD244, CCL5, CXCL9, CXCL13, MSR1, CSF3R, CYBB, and KLRK1) was defined, whose expression was higher in patients with response to ICI therapy, correlated with density of CD8<sup>+</sup>LAG3<sup>+</sup> cells in tumor microenvironment, and independently predicted better progression-free and overall survival. This 9-gene signature had similar predictive values for patients who received single-agent or combination ICI therapy and was not associated with prognosis in HCC patients who received surgery, suggesting that it may outperform other T-cell signatures for predicting efficacy of ICI therapy for HCC. For HCC patients who underwent surgery for both the primary liver and metastatic lung tumors (<i>n</i> = 31), lung metastatic HCC was associated with a higher exhausted CD8 T-cell signature, consistent with prior observation that patients with lung metastatic HCC may have higher probability of response to ICI therapy. <b><i>Conclusions:</i></b> CD8 T-cell exhaustion in tumor microenvironment may predict better efficacy of ICI therapy for HCC.

scholarly journals The Potential of T Cell Factor 1 in Sustaining CD8+ T Lymphocyte-Directed Anti-Tumor Immunity

Cancers ◽  
2021 ◽  
Vol 13 (3) ◽  
pp. 515
Author(s):  
Sungmin Jung ◽  
Jea-Hyun Baek
Keyword(s):  
T Cell ◽  
Tumor Immunity ◽  
T Lymphocyte ◽  
Critical Role ◽  
Cd8 T Cell ◽  
Immune Checkpoint Blockade ◽  
Viral Escape ◽  
T Cell Exhaustion ◽  
Cell Exhaustion ◽  
T Cell Factor

T cell factor 1 (TCF1) is a transcription factor that has been highlighted to play a critical role in the promotion of T cell proliferation and maintenance of cell stemness in the embryonic and CD8+ T cell populations. The regulatory nature of TCF1 in CD8+ T cells is of great significance, especially within the context of T cell exhaustion, which is linked to the tumor and viral escape in pathological contexts. Indeed, inhibitory signals, such as programmed cell death 1 (PD-1) and cytotoxic-T-lymphocyte-associated protein 4 (CTLA-4), expressed on exhausted T lymphocytes (TEX), have become major therapeutic targets in immune checkpoint blockade (ICB) therapy. The significance of TCF1 in the sustenance of CTL-mediated immunity against pathogens and tumors, as well as its recently observed necessity for an effective anti-tumor immune response in ICB therapy, presents TCF1 as a potentially significant biomarker and/or therapeutic target for overcoming CD8+ T cell exhaustion and resistance to ICB therapy. In this review, we aim to outline the recent findings on the role of TCF1 in T cell development and discuss its implications in anti-tumor immunity.

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