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

Banerjee, Hridesh; Nieves-Rosado, Hector M; Kulkarni, Aditi; Murter, Benjamin; Chandran, Uma; Chang, Alexander; Szymczak-Workman, Andrea L.; Vujanović, Lazar; Ferris, Robert L.; Kane, Larry

doi:10.1101/2020.07.31.230714

Cited by 6 publications

(4 citation statements)

References 60 publications

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“…As expected, the model showed a signi cantly immune-suppressive TME, consisting of increased expression of inhibitory IC proteins such as PD-1 and TIM-3 in lymphocytes. The increase in both CD25 + FoxP3 + Treg cells and PD-1 + and TIM-3 + Treg expression is associated with more suppressive activity [57]. Curcumin treatment not only reduces the size and number of lesions but also may reduce the risk of invasive cancer and increase the proportion of precancerous lesions, implying that Curcumin functions as a chemopreventive agent that inhibits cancer initiation and may also reduce cancer progression [58].…”

Section: Discussionmentioning

confidence: 99%

The effect of Curcumin on multi-level immune checkpoint blockade and T cell dysfunction in head and neck cancer

et al. 2021

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BackgroundDespite recent advances in understanding the complex immunologic dysfunction in the tumor microenvironment (TME), fewer than 20% of patients with head and neck squamous cell carcinoma (HNSCC) respond to immune checkpoint blockade (ICB). Thus, it is important to understand how inhibitory IC receptors maintain the suppressed dysfunctional TME, and to develop more effective combination immunotherapy. This study evaluated the immune-modulating effects of Curcumin, which has well-established anti-cancer and chemopreventive properties, and its long-term safety as a phytochemical drug. MethodsWe carried out the western blot and small interfering RNA (siRNA) transfection assay to evaluate the effects of Curcumin on IC ligands and IC ligands function in HNSCC. Through T-cell cytotoxicity assay and measurements of cytokine secretion, we assessed the effects of combination of Curcumin with programmed death-ligand 1 (PD-L1) Ab on cancer cell killing. Flow cytometry were used to analyze the effects of Curcumin on the expression of programmed cell death protein 1 (PD-1) and T-cell immunoglobulin and mucin-domain3 (TIM-3) on CD4, CD8 and Treg. Immuno uorescence, immunohistochemistry and western blot were used to detecte the cytokine (IFN-γ, Granzyme B), IC receptors (PD-1 and TIM-3) and its ligands (PD-L1, PD-L2, Galectin-9) in xenograft mouse model and 4nitroquinoline-1-oxide (4-NQO) oral cancer model. ResultsWe found that Curcumin decreased the expression of IC ligands such as PD-L1, PD-L2, and Galectin-9 in HNSCC, leading to regulation of epithelial-to-mesenchymal transition-associated tumor invasion.Curcumin also effectively restored the ability of CD8 + cytotoxic T cells to lyse cancer cells. To evaluate the effect of Curcumin on the TME further, the 4-NQO oral cancer model was used. Curcumin increased Tcell proliferation, tumor-in ltrating lymphocytes (TILs), and effector cytokines, and decreased the expression of PD-1, TIM-3, suppressive IC receptors and their ligands (PD-L1, PD-L2, and Galectin-9) in the TME, implying reinvigoration of the exhausted CD8 + T cells. In addition, Curcumin inhibited expression of CD4 + CD25 + FoxP3 + Treg cells as well as PD-1 and TIM-3. ConclusionsThese results show that Curcumin reinvigorates defective T cells via multiple (PD-1 and TIM-3) and multilevel (IC receptors and its ligands) IC axis suppression, thus providing a rationale to combine Curcumin with conventional targeted therapy or ICB as a multi-faceted approach for treating patients with HNSCC.

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Section: Discussionmentioning

confidence: 99%

The effect of Curcumin on multi-level immune checkpoint blockade and T cell dysfunction in head and neck cancer

et al. 2021

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“…Although these genes have been shown to promote conventional T cell dysfunction during cases of chronic viral infection ( Khan et al, 2019 ), cancer pathogenesis ( Scott et al, 2019 ), and tonic signaling in CAR-T cells ( Weber et al, 2021 ), they also play an active role in enhancing Treg immunosuppressive function ( Ukena et al, 2011 ; Sakuishi et al, 2013 ; Kurtulus et al, 2015 ; Sprouse et al, 2018 ) and hence, might be beneficial for treatment efficacy. This enhanced effector function may come at a cost, as highly suppressive TIM-3 + Tregs have impaired survival rates in vivo , notably during allograft response during transplant settings ( Gupta et al, 2012 ; Banerjee et al, 2020 ).…”

Section: Discussionmentioning

confidence: 99%

Strong Expansion of Human Regulatory T Cells for Adoptive Cell Therapy Results in Epigenetic Changes Which May Impact Their Survival and Function

Hamo

Schulze

et al. 2021

Front. Cell Dev. Biol.

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Adoptive transfer of regulatory T cells (Treg) is a promising new therapeutic option to treat detrimental inflammatory conditions after transplantation and during autoimmune disease. To reach sufficient cell yield for treatment, ex vivo isolated autologous or allogenic Tregs need to be expanded extensively in vitro during manufacturing of the Treg product. However, repetitive cycles of restimulation and prolonged culture have been shown to impact T cell phenotypes, functionality and fitness. It is therefore critical to scrutinize the molecular changes which occur during T cell product generation, and reexamine current manufacturing practices. We performed genome-wide DNA methylation profiling of cells throughout the manufacturing process of a polyclonal Treg product that has proven safety and hints of therapeutic efficacy in kidney transplant patients. We found progressive DNA methylation changes over the duration of culture, which were donor-independent and reproducible between manufacturing runs. Differentially methylated regions (DMRs) in the final products were significantly enriched at promoters and enhancers of genes implicated in T cell activation. Additionally, significant hypomethylation did also occur in promoters of genes implicated in functional exhaustion in conventional T cells, some of which, however, have been reported to strengthen immunosuppressive effector function in Tregs. At the same time, a set of reported Treg-specific demethylated regions increased methylation levels with culture, indicating a possible destabilization of Treg identity during manufacturing, which was independent of the purity of the starting material. Together, our results indicate that the repetitive TCR-mediated stimulation lead to epigenetic changes that might impact functionality of Treg products in multiple ways, by possibly shifting to an effector Treg phenotype with enhanced functional activity or by risking destabilization of Treg identity and impaired TCR activation. Our analyses also illustrate the value of epigenetic profiling for the evaluation of T cell product manufacturing pipelines, which might open new avenues for the improvement of current adoptive Treg therapies with relevance for conventional effector T cell products.

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“…Conversely, in Tregs, TIM-3 induces a metabolic shift from OXPHOS toward glycolysis while decreasing mitochondrial mass and membrane potential. TIM-3 expression in Tregs promotes tumor progression and exhaustion of CD8+ T cells enhancing their suppressive activity and IL-10 production (241).…”

Section: Tim-3/gal-9mentioning

confidence: 99%

Partners in crime: The feedback loop between metabolic reprogramming and immune checkpoints in the tumor microenvironment

et al. 2023

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The tumor microenvironment (TME) is a complex and constantly changing cellular system composed of heterogeneous populations of tumor cells and non-transformed stromal cells, such as stem cells, fibroblasts, endothelial cells, pericytes, adipocytes, and innate and adaptive immune cells. Tumor, stromal, and immune cells consume available nutrients to sustain their proliferation and effector functions and, as a result of their metabolism, produce a wide array of by-products that gradually alter the composition of the milieu. The resulting depletion of essential nutrients and enrichment of by-products work together with other features of the hostile TME to inhibit the antitumor functions of immune cells and skew their phenotype to promote tumor progression. This review briefly describes the participation of the innate and adaptive immune cells in recognizing and eliminating tumor cells and how the gradual metabolic changes in the TME alter their antitumor functions. In addition, we discuss the overexpression of the immune checkpoints and their ligands as a result of nutrient deprivation and by-products accumulation, as well as the amplification of the metabolic alterations induced by the immune checkpoints, which creates an immunosuppressive feedback loop in the TME. Finally, the combination of metabolic and immune checkpoint inhibitors as a potential strategy to treat cancer and enhance the outcome of patients is highlighted.

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

Cited by 6 publications

References 60 publications

The effect of Curcumin on multi-level immune checkpoint blockade and T cell dysfunction in head and neck cancer

The effect of Curcumin on multi-level immune checkpoint blockade and T cell dysfunction in head and neck cancer

Strong Expansion of Human Regulatory T Cells for Adoptive Cell Therapy Results in Epigenetic Changes Which May Impact Their Survival and Function

Partners in crime: The feedback loop between metabolic reprogramming and immune checkpoints in the tumor microenvironment

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