9 results on '"Imene Hamaidi"'
Search Results
2. An FGFR3/MYC positive feedback loop provides new opportunities for targeted therapies in bladder cancers
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Mélanie Mahe, Florent Dufour, Hélène Neyret‐Kahn, Aura Moreno‐Vega, Claire Beraud, Mingjun Shi, Imene Hamaidi, Virginia Sanchez‐Quiles, Clementine Krucker, Marion Dorland‐Galliot, Elodie Chapeaublanc, Remy Nicolle, Hervé Lang, Celio Pouponnot, Thierry Massfelder, François Radvanyi, and Isabelle Bernard‐Pierrot
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BET inhibitors ,bladder cancer ,FGFR3 ,MYC ,p38 ,Medicine (General) ,R5-920 ,Genetics ,QH426-470 - Abstract
Abstract FGFR3 alterations (mutations or translocation) are among the most frequent genetic events in bladder carcinoma. They lead to an aberrant activation of FGFR3 signaling, conferring an oncogenic dependence, which we studied here. We discovered a positive feedback loop, in which the activation of p38 and AKT downstream from the altered FGFR3 upregulates MYC mRNA levels and stabilizes MYC protein, respectively, leading to the accumulation of MYC, which directly upregulates FGFR3 expression by binding to active enhancers upstream from FGFR3. Disruption of this FGFR3/MYC loop in bladder cancer cell lines by treatment with FGFR3, p38, AKT, or BET bromodomain inhibitors (JQ1) preventing MYC transcription decreased cell viability in vitro and tumor growth in vivo. A relevance of this loop to human bladder tumors was supported by the positive correlation between FGFR3 and MYC levels in tumors bearing FGFR3 mutations, and the decrease in FGFR3 and MYC levels following anti‐FGFR treatment in a PDX model bearing an FGFR3 mutation. These findings open up new possibilities for the treatment of bladder tumors displaying aberrant FGFR3 activation.
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- 2018
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3. Combined nivolumab and ipilimumab with or without stereotactic body radiation therapy for advanced Merkel cell carcinoma: a randomised, open label, phase 2 trial
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Sungjune, Kim, Evan, Wuthrick, Dukagjin, Blakaj, Zeynep, Eroglu, Claire, Verschraegen, Ram, Thapa, Matthew, Mills, Khaled, Dibs, Casey, Liveringhouse, Jeffery, Russell, Jimmy J, Caudell, Ahmad, Tarhini, Joseph, Markowitz, Kari, Kendra, Richard, Wu, Dung-Tsa, Chen, Anders, Berglund, Lauren, Michael, Mia, Aoki, Min-Hsuan, Wang, Imene, Hamaidi, Pingyan, Cheng, Janis, de la Iglesia, Robbert J, Slebos, Christine H, Chung, Todd C, Knepper, Carlos M, Moran-Segura, Jonathan V, Nguyen, Bradford A, Perez, Trevor, Rose, Louis, Harrison, Jane L, Messina, Vernon K, Sondak, Kenneth Y, Tsai, Nikhil I, Khushalani, and Andrew S, Brohl
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Adult ,Skin Neoplasms ,Adolescent ,Receptors, Death Domain ,General Medicine ,Radiosurgery ,Ipilimumab ,B7-H1 Antigen ,Carcinoma, Merkel Cell ,Nivolumab ,Antineoplastic Combined Chemotherapy Protocols ,Humans ,Immune Checkpoint Inhibitors ,Biomarkers - Abstract
Merkel cell carcinoma is among the most aggressive and lethal of primary skin cancers, with a high rate of distant metastasis. Anti-programmed death receptor 1 (anti-PD-1) and programmed death ligand 1 (PD-L1) monotherapy is currently standard of care for unresectable, recurrent, or metastatic Merkel cell carcinoma. We assessed treatment with combined nivolumab plus ipilimumab, with or without stereotactic body radiotherapy (SBRT) in patients with advanced Merkel cell carcinoma as a first-line therapy or following previous treatment with anti-PD-1 and PD-L1 monotherapy.In this randomised, open label, phase 2 trial, we randomly assigned adults from two cancer sites in the USA (one in Florida and one in Ohio) to group A (combined nivolumab and ipilimumab) or group B (combined nivolumab and ipilimumab plus SBRT) in a 1:1 ratio. Eligible patients were aged at least 18 years with histologically proven advanced stage (unresectable, recurrent, or stage IV) Merkel cell carcinoma, a minimum of two tumour lesions measureable by CT, MRI or clinical exam, and tumour tissue available for exploratory biomarker analysis. Patients were stratified by previous immune-checkpoint inhibitor (ICI) status to receive nivolumab 240 mg intravenously every 2 weeks plus ipilimumab 1 mg/kg intravenously every 6 weeks (group A) or the same schedule of combined nivolumab and ipilimumab with the addition of SBRT to at least one tumour site (24 Gy in three fractions at week 2; group B). Patients had to have at least two measurable sites of disease so one non-irradiated site could be followed for response. The primary endpoint was objective response rate (ORR) in all randomly assigned patients who received at least one dose of combined nivolumab and ipilimumab. ORR was defined as the proportion of patients with a complete response or partial response per immune-related Response Evaluation Criteria in Solid Tumours. Response was assessed every 12 weeks. Safety was assessed in all patients. This trial is registered with ClinicalTrials.gov, NCT03071406.50 patients (25 in both group A and group B) were enrolled between March 14, 2017, and Dec 21, 2021, including 24 ICI-naive patients (13 [52%] of 25 group A patients and 11 [44%] of 25 group B patients]) and 26 patients with previous ICI (12 [48%] of 25 group A patients and 14 [56%] of 25 group B patients]). One patient in group B did not receive SBRT due to concerns about excess toxicity. Median follow-up was 14·6 months (IQR 9·1-26·5). Two patients in group B were excluded from the analysis of the primary endpoint because the target lesions were irradiated and so the patients were deemed non-evaluable. Of the ICI-naive patients, 22 (100%) of 22 (95% CI 82-100) had an objective response, including nine (41% [95% CI 21-63]) with complete response. Of the patients who had previously had ICI exposure, eight (31%) of 26 patients (95% CI 15-52) had an objective response and four (15% [5-36]) had a complete response. No significant differences in ORR were observed between groups A (18 [72%] of 25 patients) and B (12 [52%] of 23 patients; p=0·26). Grade 3 or 4 treatment-related adverse events were observed in 10 (40%) of 25 patients in group A and 8 (32%) of 25 patients in group B.First-line combined nivolumab and ipilimumab in patients with advanced Merkel cell carcinoma showed a high ORR with durable responses and an expected safety profile. Combined nivolumab and ipilimumab also showed clinical benefit in patients with previous anti-PD-1 and PD-L1 treatment. Addition of SBRT did not improve efficacy of combined nivolumab and ipilimumab. The combination of nivolumab and ipilimumab represents a new first-line and salvage therapeutic option for advanced Merkel cell carcinoma.Bristol Myers Squibb Rare Population Malignancy Program.
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- 2022
4. Sirtuins are crucial regulators of T cell metabolism and functions
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Imene Hamaidi and Sungjune Kim
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T-Lymphocytes ,Clinical Biochemistry ,Molecular Medicine ,Humans ,Sirtuins ,Cell Differentiation ,Molecular Biology ,Biochemistry ,Protein Processing, Post-Translational ,Metabolic Networks and Pathways - Abstract
It is well known that metabolism underlies T cell differentiation and functions. The pathways regulating T cell metabolism and function are interconnected, and changes in T cell metabolic activity directly impact the effector functions and fate of T cells. Thus, understanding how metabolic pathways influence immune responses and ultimately affect disease progression is paramount. Epigenetic and posttranslational modification mechanisms have been found to control immune responses and metabolic reprogramming. Sirtuins are NAD+-dependent histone deacetylases that play key roles during cellular responses to a variety of stresses and have recently been reported to have potential roles in immune responses. Therefore, sirtuins are of significant interest as therapeutic targets to treat immune-related diseases and enhance antitumor immunity. This review aims to illustrate the potential roles of sirtuins in different subtypes of T cells during the adaptive immune response.
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- 2021
5. Epigenetic dysregulation of immune-related pathways in cancer: bioinformatics tools and visualization
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Ryan Putney, Sungjune Kim, Anders Berglund, and Imene Hamaidi
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Epigenomics ,animal diseases ,Clinical Biochemistry ,chemical and pharmacologic phenomena ,Review Article ,Biology ,Bioinformatics ,medicine.disease_cause ,Biochemistry ,Epigenesis, Genetic ,Immune system ,Neoplasms ,Genetics research ,medicine ,Animals ,Humans ,Epigenetics ,Molecular Biology ,Immunity ,Cancer ,Computational Biology ,Epigenome ,biochemical phenomena, metabolism, and nutrition ,DNA Methylation ,medicine.disease ,Gene Expression Regulation, Neoplastic ,Immune recognition ,Cancer cell ,Molecular Medicine ,bacteria ,Disease Susceptibility ,Carcinogenesis ,Transcriptome ,Biomarkers ,Signal Transduction - Abstract
Cancer immune evasion is one of the hallmarks of carcinogenesis. Cancer cells employ multiple mechanisms to avoid immune recognition and suppress antitumor immune responses. Recently, accumulating evidence has indicated that immune-related pathways are epigenetically dysregulated in cancer. Most importantly, the epigenetic footprint of immune-related pathways is associated with the patient outcome, underscoring the crucial need to understand this process. In this review, we summarize the current evidence for epigenetic regulation of immune-related pathways in cancer and describe bioinformatics tools, informative visualization techniques, and resources to help decipher the cancer epigenome., Cancer: Bioinformatics helps identify immune system evasion Abnormal patterns of genomic chemical modification help tumors elude immunological destruction, but sophisticated computational tools could help identify and overcome these survival mechanisms. Immunotherapy can be a potent weapon against cancer, but many tumors evolve the ability to protect themselves by subduing the immune response. Sungjune Kim and colleagues at the Moffitt Cancer Center, Tampa, USA, have reviewed efforts to study how chemical alterations to DNA that affect gene expression contribute to this process. Considerable evidence indicates a role for a modification called methylation in this immune evasion, and researchers now have access to vast repositories of tumor-specific gene methylation profiles. The authors describe these data resources, and highlight some of the software tools that are helping oncologists to identify patterns in the data that might lead to better therapies.
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- 2021
6. 93 Targeting sirt2 rescues the metabolic fitness and effector functions of tumor-reactive T cells within the metabolically restricted tumor microenvironment
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Scott J. Antonia, Robert W. Engelman, Sungjune Kim, Min Liu, Jiqiang Yao, Anders Berglund, John M. Koomen, James J. Mulé, Ben C. Creelan, Min-Hsuan Wang, Nayoung Kim, Bin Fang, Lin Zhang, Jose R. Conejo-Garcia, Cristina Iclozan, Imene Hamaidi, and Sean Yoder
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chemistry.chemical_compound ,Tumor microenvironment ,Immune system ,medicine.anatomical_structure ,chemistry ,Effector ,ELISPOT ,T cell ,Cancer research ,medicine ,Cytotoxic T cell ,DAPI ,SIRT2 - Abstract
Background The majority of cancer patients remain refractory to existing cancer immunotherapies. Despite the growing evidence that dysregulated metabolism contributes to the exhaustion of tumor-infiltrating T lymphocytes (TILs) and the loss of their effector functions within the metabolically restricted tumor microenvironment (TME), actionable targets to rescue metabolic fitness and anti-tumor activity of TILs remain elusive.Memory T (TM) cells and TILs rely on fatty acid catabolism to preserve their effector functions due to nutrient competition for glucose with tumor cells. Therefore, enhancing fatty acid catabolism of TILs represents an attractive strategy to increase the efficacy of immunotherapies.Sirt2 is an NAD+ dependent histone deacetylase. We previously showed that upregulation of Sirt2 in human TILs negatively correlates with response to TIL therapy in advanced non-small cell lung cancer (NSCLC) and Sirt2 deficiency leads to hyper-reactive T cells with superior antitumor activity. Methods Sirt2 expression was analyzed by flow cytometry and Western blot. The role of Sirt2 in tumor immunity was studied using in vivo B16F10 tumor challenge models as well as ex vivo analysis including RNA-sequencing, CFSE proliferation assay, DAPI/AnnexinV staining, IFN-γ ELISpot assay, intracellular staining of effector molecules and LDH cytotoxicity assay on WT versus Sirt2KO T cells. Molecular partners of Sirt2 were identified using mass spectrometry (MS) and Co-immunoprecipitation analyses. The role of Sirt2 in T cell metabolism was investigated using seahorse bioanalyzer and LC-MS/MS Metabolomic profiling. AGK2, a Sirt2 selective inhibitor, was used for Sirt2 blockade in human T cells. Results Sirt2 expression is upregulated during T cell activation, TM stage, and within the TME. Our molecular studies revealed that Sirt2 negatively impacts the acetylation status and the activity of the trifunctional protein, the key enzyme of fatty acid oxidation (FAO). Accordingly, Sirt2 deficiency enhanced FAO and metabolic fitness of activated T cells and mouse TILs isolated from B16F10 tumor nodules. As a consequence of enhanced FAO, Sirt2 deficient mice displayed increased accumulation of TM cells, which was associated with decreased apoptosis and increased survival after tumor challenge leading to superior tumor rejection. Most importantly, pharmacologic inhibition of Sirt2 in human TILs isolated from NSCLC patients enhanced their metabolic fitness and cytotoxic activity against their autologous tumor cells. Conclusions Our findings indicate Sirt2 as a suppressor of T cell metabolism amenable to therapeutic targeting, and Sirt2 inhibition reprograms T cell metabolic fitness to optimally sustain their effector function within the hypoglycemic TME, thus, leading to an effective anti-tumor immune response. Acknowledgements This work was supported in part by K08 CA194273, ACS IRG-17-173-22, NCI Cancer Center Support Grant (P30-CA076292) and the Moffitt Foundation.
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- 2020
7. 907 Modulation of tumor immunogenicity by DNA methylation of immune synapse genes in cancers
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Matthew Mills, James J. Mulé, Ryan Putney, Anders Berglund, Sungjune Kim, and Imene Hamaidi
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Pharmacology ,Cancer Research ,Oncology ,Immunogenicity ,Immunology ,DNA methylation ,Cancer research ,Molecular Medicine ,Immunology and Allergy ,Biology ,Gene ,Immunological synapse - Abstract
BackgroundCancer immunotherapy represents a major paradigm shift in cancer care. Despite such breakthrough, majority of cancer patients remains refractory to existing immunotherapeutic modalities highlighting the inherent capacity of tumors to escape immunosurveillance mechanisms. Frequently, cancer cells utilize the epigenetic machinery to silence tumor suppressors or activate oncogenes for survival and proliferation. Likewise, tumor cells might employ the epigenetic reprogramming of immune-related pathways to evade the immune system. Methylation is one of the major epigenetic mechanisms modulating gene transcription. Thus, we investigated the methylation profile of both co-stimulatory and immune checkpoint genes in cancer.MethodsData from The Cancer Genome Atlas (TCGA) were used for methylation profiling and RNA-sequencing analysis. Twenty-six epithelial cancer cell lines with more than 3 mock and three 5-azacitidine–treated samples were selected for analysis from the GSE57342 dataset. t-distributed stochastic neighbor embedding (t-SNE) was calculated using 247 probes for the selected 20 genes across all TCGA samples. t-SNE analysis was performed on 8,186 solid tumors and 745 normal adjacent tissues for methylation levels for all probes. For principal component analysis, first and second principal components were used to represent the overall methylation status for 8,931 tumor and normal samples in the TCGA database. Survival analyses were retrieved from a prior publication.1ResultsWe found that methylation profile of immune synapse genes is distinct in tumor versus normal adjacent tissue. Interestingly, our results demonstrate hypermethylation of co-stimulatory genes such as CD40 and hypo-methylation of immune checkpoint genes such as HHLA2 and PDL1 across multiple tumor types in comparison with the normal adjacent tissue. In addition, an inverse correlation between methylation and gene expression was manifest among tumor and normal adjacent tissue, confirming the epigenetic mechanism of gene suppression by gene methylation. Furthermore, we observed a reversal of hypermethylation of the co-stimulatory genes including CD40 by the demethylating agent 5-azacytidine in the data set of 26 epithelial cancer cell lines. Finally, we found that that hypomethylation of co-stimulatory genes within the immune synapse correlates with functional T cell recruitment to the tumor microenvironment and is followed by a favorable clinical outcome in melanoma patients.ConclusionsOur finding unveils methylation of immune synapse genes as a crucial driver of the immune evasive phenotype of cancer cells. Notably, identification of actionable targets to restore tumor immunogenicity is an attractive strategy in combination with immune checkpoint blockade.AcknowledgementsThis work was supported by NIH grant K08 CA194273, the Immunology Innovation Fund, an NCI Cancer Center Support grant, (P30-CA076292), the Miriam and Sheldon G. Adelson Foundation, and the Moffitt Foundation.ReferenceLiu J, Lichtenberg T, Hoadley KA, Poisson LM, Lazar AJ, Cherniack AD, Kovatich AJ, Benz CC, Levine DA, Lee AV, Omberg L, Wolf DM, Shriver CD, Thorsson V, Cancer Genome Atlas Research N, Hu H. An integrated TCGA pan-cancer clinical data resource to drive high-quality survival outcome analytics. Cell 2018;173(2):400–16 e11.
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- 2021
8. Abstract 1635: Sirt2 blockade promotes T cell metabolism and restores the anti-tumor immunity
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Ben C. Creelan, Lin Zhang, Nayoung Kim, Anders Berglund, John M. Koomen, Scott J. Antonia, Sungjune Kim, Sean J. Yoder, Robert W. Engelman, Jose R. Conejo-Garcia, Jiqiang Yao, Min Hsuan Wang, James J. Mulé, Imene Hamaidi, Min Liu, Bin Fang, and Cristina Iclozan
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Cancer Research ,medicine.anatomical_structure ,Oncology ,Antitumor immunity ,Chemistry ,T cell ,Cancer research ,medicine ,Metabolism ,SIRT2 ,Blockade - Abstract
Background: The majority of cancer patients remain refractory to existing cancer immunotherapies. Despite the growing evidence that dysregulated metabolism contributes to the exhaustion of tumor-infiltrating T lymphocytes (TILs) and the loss of their effector functions within the metabolically restricted tumor microenvironment (TME), actionable targets to rescue metabolic fitness and anti-tumor activity of TILs remain elusive. Sirt2 is an NAD+ dependent histone deacetylase and conflicting evidences suggest its tumor-suppressor and oncogenic roles. In inflammatory response, Sirt2 suppresses inflammation via negative regulation of NF-κB subunit; however, the role of Sirt2 in tumor immunity has not been described. Method: Human TILs from non-small cell lung cancer (NSCLC) tumor samples and matched peripheral blood T cells were analyzed for Sirt2 expression by flow cytometry. The role of Sirt2 in anti-tumor immunity was studied by in vivo B16F10 tumor challenge in Wild-type (Wt) and Sirt2 knockout (Sirt2KO) mice. The role of Sirt2 in T cell effector functions was investigated ex vivo by CFSE proliferation assay, IFN-γ ELISpot assay, intracellular staining of effector markers and LDH cytotoxicity assay on Wt versus Sirt2KO T cells. Sirt2 targets were identified using mass spectrometry (MS) and Co-immunoprecipitation analyses. T cells metabolic changes were investigated using seahorse bioanalyzer and LC-MS/MS Metabolomic profiling. Sirt2 blockade in human T cells was performed using AGK2, a Sirt2 selective inhibitor. Result: We show that Sirt2 expression is upregulated within the TME, and its upregulation in human TILs is associated with a poor clinical response to immunotherapy in a phase I clinical trial in advanced NSCLC. We also show that, Sirt2 deficiency in mice boosts T cell effector functions and tumor rejection in vivo. Our molecular and metabolomic studies revealed multiple metabolic pathways as Sirt2 targets including glycolysis, TCA-cycle, FAO and glutaminolysis. We found that Sirt2 deacetylase deficiency increased acetylation and enzymatic activity of key metabolic enzymes leading to a hyper metabolic status of T cells. Finally pharmacologic inhibition of Sirt2 in human TILs isolated from NSCLC patients enhances their metabolic fitness and effector functions. Conclusion Our findings indicate Sirt2 as a master suppressor of T cell metabolism amenable to therapeutic targeting and Sirt2 inhibition reprograms T cell metabolic fitness to optimally sustain their effector function within the metabolically challenging TME, thus, leading to an effective anti-tumor immune response. Citation Format: Imene Hamaidi, Lin Zhang, Nayoung Kim, Min Hsuan Wang, Cristina Iclozan, Bin Fang, Min Liu, John M. Koomen, Anders E. Berglund, Sean J. Yoder, Jiqiang Yao, Robert W. Engelman, Ben C. Creelan, Jose R. Conejo-Garcia, James J. Mulé, Scott J. Antonia, Sungjune Kim. Sirt2 blockade promotes T cell metabolism and restores the anti-tumor immunity [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 1635.
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- 2021
9. Sirt2 Inhibition Enhances Metabolic Fitness and Effector Functions of Tumor-Reactive T Cells
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Min-Hsuan Wang, Ben C. Creelan, Lin Zhang, Cristina Iclozan, Bin Fang, Imene Hamaidi, Robert W. Engelman, Min Liu, Nayoung Kim, Anders Berglund, Scott J. Antonia, James J. Mulé, Sungjune Kim, Sean J. Yoder, Jose R. Conejo-Garcia, John M. Koomen, and Jiqiang Yao
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0301 basic medicine ,Lung Neoplasms ,Physiology ,T-Lymphocytes ,Antineoplastic Agents ,Oxidative phosphorylation ,SIRT2 ,Article ,Mice ,03 medical and health sciences ,Sirtuin 2 ,0302 clinical medicine ,Downregulation and upregulation ,Carcinoma, Non-Small-Cell Lung ,Animals ,Humans ,Glycolysis ,Enzyme Inhibitors ,Molecular Biology ,Cells, Cultured ,Tumor microenvironment ,Glutaminolysis ,Effector ,Chemistry ,Cell Biology ,Cell biology ,Mice, Inbred C57BL ,030104 developmental biology ,Reprogramming ,030217 neurology & neurosurgery - Abstract
Summary Dysregulated metabolism is a key driver of maladaptive tumor-reactive T lymphocytes within the tumor microenvironment. Actionable targets that rescue the effector activity of antitumor T cells remain elusive. Here, we report that the Sirtuin-2 (Sirt2) NAD+-dependent deacetylase inhibits T cell metabolism and impairs T cell effector functions. Remarkably, upregulation of Sirt2 in human tumor-infiltrating lymphocytes (TILs) negatively correlates with response to TIL therapy in advanced non-small-cell lung cancer. Mechanistically, Sirt2 suppresses T cell metabolism by targeting key enzymes involved in glycolysis, tricarboxylic acid-cycle, fatty acid oxidation, and glutaminolysis. Accordingly, Sirt2-deficient murine T cells exhibit increased glycolysis and oxidative phosphorylation, resulting in enhanced proliferation and effector functions and subsequently exhibiting superior antitumor activity. Importantly, pharmacologic inhibition of Sirt2 endows human TILs with these superior metabolic fitness and effector functions. Our findings unveil Sirt2 as an unexpected actionable target for reprogramming T cell metabolism to augment a broad spectrum of cancer immunotherapies.
- Published
- 2020
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