18 results on '"Velica, Pedro"'
Search Results
2. Oxygen levels at the time of activation determine T cell persistence and immunotherapeutic efficacy
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Cunha, Pedro P, primary, Minogue, Eleanor, additional, Krause, Lena CM, additional, Hess, Rita M, additional, Bargiela, David, additional, Wadsworth, Brennan J, additional, Barbieri, Laura, additional, Brombach, Carolin, additional, Foskolou, Iosifina P, additional, Bogeski, Ivan, additional, Velica, Pedro, additional, and Johnson, Randall S, additional
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- 2023
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3. Cd8+ T-cell Depletion Abolishes The Anti-metastatic Effects Of Voluntary Running In A Mouse Model Of Breast Cancer: 1251 Board #377 May 27 2:30 PM - 4:00 PM
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Rundqvist, Helene, Barbieri, Laura, Velica, Pedro, Mijwel, Sara, Östman, Arne, and Johnson, Randall
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- 2020
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4. Redirection to the bone marrow improves T cell persistence and antitumor functions
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Khan, Anjum B., Carpenter, Ben, Sousa, Pedro Santos e., Pospori, Constandina, Khorshed, Reema, Griffin, James, Velica, Pedro, Zech, Mathias, Ghorashian, Sara, Thomas, Calum ForresSharyn, Anton, Sara Gonzalez, Ahmadi, Maryam, Holler, Angelika, Flutter, Barry, Ramirez-Ortiz, Zaida, Means, Terry K., Stauss, Clare L. BenneHans, Morris, Emma, Celso, Cristina Lo, and Chakraverty, Ronjon
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Cancer treatment -- Research ,Genetic engineering -- Methods -- Health aspects ,Bone marrow -- Physiological aspects -- Health aspects ,Cancer research ,Immunotherapy -- Research ,T cells -- Genetic aspects -- Health aspects ,Health care industry - Abstract
A key predictor for the success of gene-modified T cell therapies for cancer is the persistence of transferred cells in the patient. The propensity of less differentiated memory T cells to expand and survive efficiently has therefore made them attractive candidates for clinical application. We hypothesized that redirecting T cells to specialized niches in the BM that support memory differentiation would confer increased therapeutic efficacy. We show that overexpression of chemokine receptor CXCR4 in [CD8.sup.+] T cells ([T.sup.CXCR4]) enhanced their migration toward vascular-associated [CXCL12.sup.+] cells in the BM and increased their local engraftment. Increased access of [T.sup.CXCR4] to the BM microenvironment induced IL-15-dependent homeostatic expansion and promoted the differentiation of memory precursor-like cells with low expression of programmed death-1, resistance to apoptosis, and a heightened capacity to generate polyfunctional cytokine-producing effector cells. Following transfer to lymphoma-bearing mice, [T.sup.CXCR4] showed a greater capacity for effector expansion and better tumor protection, the latter being independent of changes in trafficking to the tumor bed or local out-competition of regulatory T cells. Thus, redirected homing of T cells to the BM confers increased memory differentiation and antitumor immunity, suggesting an innovative solution to increase the persistence and functions of therapeutic T cells., Introduction The effector functions of T cells can be redirected against tumor antigens by gene transfer of T cell receptors (TCRs) or chimeric antigen receptors (CARs) to create large numbers [...]
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- 2018
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5. The S enantiomer of 2-hydroxyglutarate increases central memory CD8 populations and improves CAR-T therapy outcome
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Foskolou, Iosifina P, Barbieri, Laura, Vernet, Aude, Bargiela, David, Cunha, Pedro P, Velica, Pedro, Suh, Eunyeong, Pietsch, Sandra, Matuleviciute, Rugile, Rundqvist, Helene, McIntyre, Dominick, Smith, Ken GC, Johnson, Randall S, Foskolou, Iosifina [0000-0003-1874-6356], Pacheco de Jesus da Cunha, Pedro [0000-0002-3814-6289], Pietsch, Sandra [0000-0001-6398-253X], Matuleviciute, Rugile [0000-0001-5618-5700], McIntyre, Dominick [0000-0002-0269-6545], Smith, Kenneth [0000-0003-3829-4326], Johnson, Randall [0000-0002-4084-6639], and Apollo - University of Cambridge Repository
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Glutarates ,Mice ,Receptors, Chimeric Antigen ,Immunobiology and Immunotherapy ,Receptors, Antigen, T-Cell ,Animals ,Humans ,CD8-Positive T-Lymphocytes ,human activities ,Immunotherapy, Adoptive - Abstract
Cancer immunotherapy is advancing rapidly and gene-modified T cells expressing chimeric antigen receptors (CARs) show particular promise. A challenge of CAR-T cell therapy is that the ex vivo-generated CAR-T cells become exhausted during expansion in culture, and do not persist when transferred back to patients. It has become clear that naive and memory CD8 T cells perform better than the total CD8 T-cell populations in CAR-T immunotherapy because of better expansion, antitumor activity, and persistence, which are necessary features for therapeutic success and prevention of disease relapse. However, memory CAR-T cells are rarely used in the clinic due to generation challenges. We previously reported that mouse CD8 T cells cultured with the S enantiomer of the immunometabolite 2-hydroxyglutarate (S-2HG) exhibit enhanced antitumor activity. Here, we show that clinical-grade human donor CAR-T cells can be generated from naive precursors after culture with S-2HG. S-2HG-treated CAR-T cells establish long-term memory cells in vivo and show superior antitumor responses when compared with CAR-T cells generated with standard clinical protocols. This study provides the basis for a phase 1 clinical trial evaluating the activity of S-2HG-treated CD19-CAR-T cells in patients with B-cell malignancies.
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- 2020
6. The S enantiomer of 2-hydroxyglutarate increases central memory CD8 populations and improves CAR-T therapy outcome
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Foskolou, Iosifina P., primary, Barbieri, Laura, additional, Vernet, Aude, additional, Bargiela, David, additional, Cunha, Pedro P., additional, Velica, Pedro, additional, Suh, Eunyeong, additional, Pietsch, Sandra, additional, Matuleviciute, Rugile, additional, Rundqvist, Helene, additional, McIntyre, Dominick, additional, Smith, Ken G. C., additional, and Johnson, Randall S., additional
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- 2020
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7. Lactate Potentiates Differentiation and Expansion of Cytotoxic T Cells
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Rundqvist, Helene, primary, Velica, Pedro, additional, Barbieri, Laura, additional, Gameiro, Paulo, additional, Cunha, Pedro P., additional, Gojkovic, Milos, additional, Bargiela, David, additional, Mijwel, Sara, additional, Ahlstedt, Emil, additional, Foskolou, Iosifina, additional, Ruiz-Perez, Maria Victoria, additional, Arsenian-Henriksson, Marie, additional, Ule, Jernej, additional, Östman, Arne, additional, and Johnson, Randall S., additional
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- 2019
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8. Safety and efficacy of Tet-regulated IL-12 expression in cancer-specific T cells
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Alsaieedi, Ahdab, primary, Holler, Angelika, additional, Velica, Pedro, additional, Bendle, Gavin, additional, and Stauss, Hans J., additional
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- 2018
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9. Targeting therapeutic T cells to the bone-marrow niche
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Khan, Anjum Bashir, primary, Carpenter, Benjamin, additional, Santos e Sousa, Pedro, additional, Velica, Pedro, additional, Zech, Mathias, additional, Bennett, Clare, additional, Stauss, Hans, additional, Morris, Emma, additional, and Chakraverty, Ronjon, additional
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- 2017
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10. Abstract A12: The immune composition of a spontaneous mouse breast cancer
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Velica, Pedro, primary, Rundqvist, Helene, additional, Gojkovic, Milos, additional, and Johnson, Randall S., additional
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- 2016
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11. T Cell Tuning for Tumour Therapy: Enhancing Effector Function and Memory Potential of Therapeutic T cells
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Zech, Mathias, primary, Velica, Pedro, additional, and Stauss, Hans, additional
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- 2015
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12. T Cells Engineered For Resistance To Mycophenolate Mofetil Demonstrate Enhanced Expansion and Improved Tumour Control In Immunosuppressed Hosts
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Griffin, James Edward, primary, Xue, Shoa-An, additional, Carpenter, Benjamin J, additional, Velica, Pedro, additional, Holler, Angelika, additional, Ghorashian, Sara, additional, Nicholson, Emma, additional, Pule, Martin, additional, and Chakraverty, Ronjon, additional
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- 2013
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13. Tuning Of mTOR In Therapeutic T Cells As A Strategy To Manufacture Effector and Memory T Cells
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Hans J. Stauss, Mathias Zech, Velica Pedro, and Ronjon Chakraverty
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CD40 ,ZAP70 ,T cell ,Immunology ,CD28 ,Cell Biology ,Hematology ,Biology ,Biochemistry ,Cell biology ,Interleukin 21 ,medicine.anatomical_structure ,medicine ,biology.protein ,Cytotoxic T cell ,IL-2 receptor ,Interleukin 3 - Abstract
Retroviral gene transfer of T cell receptors (TCRs) or chimeric-antigen receptors has been successfully used to redirect T cell specificity to tumor antigens and has shown promising results in clinical trials for patients with melanoma and B cell malignancies. Successful therapy relies not only on the generation of an efficient effector response but also in the ability of T cells to engraft and persist during and after cancer rejection. Yet, both aspects can be compromised. On the one hand, effector T cells can be disarmed in vivo by the immunosuppressive environment of the tumor, where the depletion of key nutrients (glucose, arginine, etc.) and the predominance of inhibitory signals (TGF-β, PD-L1, etc.) dampen their functions. On the other hand, current retroviral gene transfer protocols require T cells to be activated and expanded ex vivo,driving terminal effector differentiation at the expense of the capacity for self-renewal (“stemness”). This may prevent the generation of long-term protective memory and compromise therapeutic success. The mechanistic target of rapamycin (mTOR) pathway has recently emerged as a driver of effector differentiation in CD8 T cells by acting as a signalling bridge between extracellular stimuli and effector differentiation. Whilst high doses of rapamycin are known to be immunosuppressive, a low dose regimen increases memory output after a viral challenge without impairing viral clearance. These and other studies suggest that mTOR can be used as a rheostat to regulate T cell differentiation to clinical advantage. Using a mouse model of TCR gene therapy we aimed to produce T cells in which the mTOR pathway is either hyperactive, in order to generate ‘super-effectors’ that can function in the tumor microenvironment, or hypoactive in order to preserve “stemness”, increase engraftment and produce better recall immunity. To this purpose we transferred genes into therapeutic T cells encoding either (1) an mTOR activator, RHEB (Ras homolog enriched in brain) or (2) an mTOR inhibitor, PRAS40 (proline-rich Akt substrate 40 kDa). Upon stimulation in vitro,the phosphorylation of ribosomal protein S6, an mTOR downstream target, was increased in RHEB-expressing cells and decreased in PRAS40-expressing cells. RHEB T cells demonstrated a greater propensity than controls for blast formation, lower expression of L-selectin, increased IFN-g production and resistance to TGF-b. In contrast, PRAS40 T cells were smaller in size, expressed higher surface levels of L-selectin and had reduced but not ablated production of IFN-g, IL-2 and TNF-a production. In vivo, RHEB T cells co-transduced with a tumor-specific TCR showed increased initial expansion that was associated with increased tumor protection. However, this was followed by a steep decrease in T cell numbers compared to control cells, with preliminary experiments indicating that RHEB cells produced a less robust re-call response upon antigenic re-challenge. In contrast, PRAS40 cells failed to expand in vivo or to infiltrate tumors, resulting in complete lack of protection. Yet, the few PRAS40 cells remaining in circulation were predominately high for L-selectin, IL-7Ra and Sca-1 (markers associated with ‘stemness’). These results demonstrated that constitutive suppression of mTOR was of no therapeutic advantage. To circumvent this, we developed a doxycycline (DOX)-inducible PRAS40 vector in which mTOR suppression in T cells can be temporally controlled in vivo. Unlike the constitutive vector used previously, with the DOX-ON system the level of mTOR suppression was lower and furthermore, could be applied only during the period of antigen exposure. Thus, when DOX was added during tumor challenge, PRAS40-expressing T cells could reject tumor as well as controls. However, after DOX was withdrawn and transgene expression turned off, increased numbers of therapeutic T cells were found in peripheral blood. When re-challenged, these T cells produced a stronger recall response relative to cells in which mTOR had not been suppressed initially. Thus, our results show that genetic manipulation of mTOR can be used to alter the intrinsic properties of T cells and direct either their effector or memory differentiation. This approach maybe useful in designing better therapeutic immunotherapeutic strategies according to the type of T cell response required in vivo. Disclosures: No relevant conflicts of interest to declare.
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- 2013
14. T Cell Tuning for Tumour Therapy: Enhancing Effector Function and Memory Potential of Therapeutic T cells
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H. Zech, Mathias, Velica, Pedro, and J. Stauss, Hans
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The genetic engineering of T cells can lead to enhanced immune-mediated tumour destruction and harbors a great potential for the treatment of cancer. Recent efforts have centered on the design of receptors to re-direct the specificity of T cells towards tumour antigens by means of viral gene transfer. This strategy has shown great success in a number of phase one clinical trials. However, there are still challenges to overcome. On the one hand, T cell function can be further improved to optimize the therapeutic outcome. On the other hand, so called safety switches are required to deal with possible on and off target toxicities. In this review, we will give a brief summary of the success and risks of T cell gene therapy before discussing in detail current strategies to enhance effector function, persistence and safety of adoptively transferred T cells.
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- 2015
15. Safety and efficacy of Tet-regulated IL-12 expression in cancer-specific T cells.
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Alsaieedi, Ahdab, Holler, Angelika, Velica, Pedro, Bendle, Gavin, and Stauss, Hans J.
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T cells ,GENETIC transformation ,MELANOMA ,IMMUNOTHERAPY ,TUMOR growth - Abstract
We explored whether engineering of T cell specificity and effector function improves immunotherapy of solid tumors. Although IL-12 can enhance cancer immunity, a strategy of safe IL-12 delivery without toxicity is currently lacking. We engineered T cells to express IL-12 controlled by the NFAT promoter responsive to TCR stimulation, or by the Tet-On promoter responsive to doxycycline. In vivo, NFAT-engineered T cells caused lethal toxicity, while Tet-engineered T cells were safe in the absence of doxycycline. Combining gene transfer of the melanoma-specific TRP2-TCR with Tet-IL-12 engineering revealed that temporal induction of IL-12 was essential to inhibit the growth of B16F10 melanoma tumors. Induced IL-12 increased the number of tumor-infiltrating T cells and also prevented the down-modulation of the TRP2-TCR and the associated up-regulation of the PD1 marker that was observed in the absence of IL-12. In addition, temporal induction of IL-12 expression also increased the number of plasmacytoid DC in the tumor micro-environment. We show that repeated induction of IL-12 can be used to enhance control of tumor growth without encountering systemic toxicity. The observation that TCR engineering combined with Tet-regulated IL-12 expression can achieve tumor immunity without the side effects that are usually associated with the in vivo use of IL-12 warrants translation of this concept into the clinic. [ABSTRACT FROM AUTHOR]
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- 2019
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16. Modified Hypoxia-Inducible Factor Expression in CD8+ T Cells Increases Antitumor Efficacy
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Johnson, Randall, Velica, Pedro, Cunha, Pedro, Vojnovic, Nikola, Foskolou, Iosifina, Bargiela, David, Gojkovic, Milos, and Rundqvist, Helene
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3. Good health - Abstract
Adoptive transfer of antitumor cytotoxic T cells is an emerging form of cancer immunotherapy. A key challenge to expanding the utility of adoptive-cell therapies is how to enhance the survival and function of the transferred T cells. Immune-cell survival requires adaptation to different microenvironments, and particularly to the hypoxic milieu of solid tumors. The hypoxia-inducible factor (HIF) transcription factors are an essential aspect of this adaptation. In this study, we undertook experiments to define structural determinants of HIF that potentiate antitumor efficacy in cytotoxic T cells. We first created retroviral vectors to deliver ectopic expression of HIF1ɑ and HIF2ɑ in mouse CD8+ T cells, together or individually, and with or without sensitivity to the oxygen-dependent HIFɑ inhibitors Von Hippel Lindau (VHL) and Factor Inhibiting HIF (FIH). HIF2ɑ, but not HIF1ɑ, drove broad transcriptional changes in CD8+ T cells, resulting in increased cytotoxic differentiation and cytolytic function against tumor targets. A specific mutation replacing the hydroxyl group–acceptor site for FIH in HIF2ɑ gave rise to the most effective antitumor T cells after adoptive transfer in vivo. In addition, co-delivering an FIH-insensitive form of HIF2ɑ with an anti-CD19 chimeric antigen receptor greatly enhanced cytolytic function of human CD8+ T cells against lymphoma cells both in vitro and in a xenograft adoptive transfer model. These experiments point to a means to increase the antitumor efficacy of therapeutic CD8+ T cells via ectopic expression of the HIF transcription factor.
17. Cytotoxic T-cells mediate an exercise-induced reduction in tumor growth
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Johnson, Randall, Rundqvist, Helene, Velica, Pedro, Barbieri, Laura, Gameiro, Paulo, Bargiela, David, Gojkovic, Milos, Mijwel, Sara, Reitzner, Stefan, Wulliman, David, Ahlstedt, Emil, Ule, Jernej, and Östman, Arne
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exercise ,Carcinogenesis ,3. Good health ,immunology ,Mice ,inflammation ,Cell Line, Tumor ,Physical Conditioning, Animal ,Animals ,Female ,human ,immunotherapy ,metabolism ,mouse ,cancer biology ,T-Lymphocytes, Cytotoxic - Abstract
Exercise has a wide range of systemic effects. In animal models, repeated exertion reduces malignant tumor progression, and clinically, exercise can improve outcome for cancer patients. The etiology of the effects of exercise on tumor progression are unclear, as are the cellular actors involved. We show here that in mice, exercise-induced reduction in tumor growth is dependent on CD8+ T cells, and that metabolites produced in skeletal muscle and excreted into plasma at high levels during exertion in both mice and humans enhance the effector profile of CD8+ T-cells. We found that activated murine CD8+ T cells alter their central carbon metabolism in response to exertion in vivo, and that immune cells from trained mice are more potent anti-tumor effector cells when transferred into tumor-bearing untrained animals. These data demonstrate that CD8+ T cells are metabolically altered by exercise in a manner that acts to improve their anti-tumoral efficacy.
18. The role of hypoxia in T cell function and immunotherapy
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Pacheco de Jesus da Cunha, Pedro Miguel, Johnson, Randall S., Branco, Cristina, and Velica, Pedro
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CAR-T cell therapy ,CD8+ T cells ,Glutarate ,Hypoxia ,Immunology ,Immunometabolism ,Immunotherapy ,Nitric oxide - Abstract
Oxygen deprivation (hypoxia) is an important immunosuppressive mechanism in cancer. The lack of proper blood supply and a high local metabolic demand depletes immune cells of key metabolites including oxygen. Tumour hypoxia is particularly hostile to antitumour cytotoxic CD8+ T cell function by repressing clonal expansion and by eliciting immune checkpoint mechanisms. However, T cells cultured ex vivo at low levels of oxygen outperform ambient oxygen-cultured counterparts in terms of antitumour cytotoxic function following adoptive cell transfer to a tumour-bearing host. This indicates that hypoxia can play a physiological role in regulating and, depending on the context, boosting T cell function. This dissertation is divided into 3 chapters, each dedicated to describing different physiological roles of hypoxia in CD8+ T cells. Chapter 1 addresses the role of oxygen sensing by the HIF pathway in fueling the hypoxia-driven increase in CD8+ T cell function in adoptive cell transfer settings. Increased HIF signalling achieved through genetic or pharmacological manipulation of the HIF pathway shaped T cell function and differentiation in a similar manner to exposure to low oxygen tensions. Exacerbated HIF signalling was immunosuppressive whereas a controlled or temporary increase in HIF activity was immunomodulatory and improved the cytotoxic function of CAR-T cells. A single day of hypoxia-conditioning during T cell activation followed by 6 days of expansion in ambient oxygen, was sufficient to modulate metabolism, differentiation and to improve in vivo antitumour cytotoxicity of CAR-T cells, thus showing the power of oxygen tensions in shaping T cell function. Chapter 2 focuses on the metabolic adaptation to low oxygen in CD8+ T cells, and characterises the immunomodulatory role of glutarate, a newly discovered hypoxia-induced metabolite. Glutarate was found to inhibit α-ketoglutarate dependent reactions and to modulate T cell differentiation and improve antitumour CD8+T cell function. Administration of esterified glutarate in tumour-bearing animals significantly improved infiltration of CD8+ T cells in tumours and extended animal survival, thus revealing the potential of glutarate to be used as a metabolic target. Chapter 3 describes the role of nitric oxide, another hypoxia-induced metabolite, in T cell function. Nitric oxide was found to be endogenously produced by T cells and to mediate their tissue infiltration and antitumour function. Overall, the data presented here show how oxygen tensions can profoundly shape T cell function through modulation of T cell differentiation and metabolism and informs about new strategies of T cell modulation that can improve immunotherapy.
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- 2022
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