Distinct Signaling of Coreceptors Regulates Specific Metabolism Pathways and Impacts Memory Development in CAR T Cells

Kawalekar, Omkar U.; O’Connor, Roddy S.; Fraietta, Joseph A.; Guo, Lili; McGettigan, Shannon E.; Posey, Avery D.; Patel, Prachi; Guedan, Sonia; Scholler, John; Keith, Brian; Snyder, Nathaniel W.; Blair, Ian A.; Milone, Michael C.; June, Carl H.

doi:10.1016/j.immuni.2016.01.021

Cited by 936 publications

(691 citation statements)

References 53 publications

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“…This could reflect an advantage of CD137 in inducing mitochondrial respiration, in addition to glycolysis. This is consistent with previous observations comparing the cytoplasmic tails of CD28 and CD137 in CARs (19). CD28 plus CD137 dual costimulation further increased Mitotracker content (Fig.…”

Section: Experiments Human Cd8supporting

confidence: 93%

“…In this regard, a CD137-containing CAR did not increase glycolysis (19), perhaps suggesting differences between the chimeric and naturally occurring molecules.…”

Section: Discussionmentioning

confidence: 88%

“…Previous observations with the CD137 cytoplasmic tail built into anti-CD19 chimeric antigen receptors (19) suggested prominent effects of CD137 on mitochondria. However, CD3ζ placed in tandem in such constructions made it very difficult to ascertain if these functions were the result of the artificial chimeric molecules or an effect mediated by the naturally occurring moieties.…”

Section: Discussionmentioning

confidence: 92%

“…The cytoplasmic tail of CD137 has been introduced in clinically successful anti-CD19 chimeric antigen receptors (CARs) (17,18). In this setting, the inclusion of the CD137 cytoplasmic tail results in increased mitochondrial biogenesis and a more powerful respiratory capacity as compared to CARs containing the CD28 signaling domain (19).…”

Section: Introductionmentioning

confidence: 99%

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Mitochondrial Morphological and Functional Reprogramming Following CD137 (4-1BB) Costimulation

Teijeira

Labiano

Garasa

et al. 2018

Cancer Immunology Research

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T and NK lymphocytes express CD137 (4-1BB), a costimulatory receptor of the TNFR family whose function is exploitable for cancer immunotherapy. Mitochondria regulate the function and survival of T lymphocytes. Herein, we show that CD137 costimulation provided by agonist mAb and CD137L (4-1BBL) induced mitochondria enlargement that resulted in enhanced mitochondrial mass and transmembrane potential in human and mouse CD8+ T cells. Such mitochondrial changes increased T-cell respiratory capacities and were critically dependent on mitochondrial fusion protein OPA-1 expression. Mass and function of mitochondria in tumor-reactive CD8+ T cells from cancer-bearing mice were invigorated by agonist mAb to CD137, whereas mitochondrial baseline mass and function were depressed in CD137-deficient tumor reactive T cells. Tumor rejection induced by the synergistic combination of adoptive T-cell therapy and agonistic anti-CD137 was critically dependent on OPA-1 expression in transferred CD8+ T cells. Moreover, stimulation of CD137 with CD137 mAb in short-term cultures of human tumor-infiltrating lymphocytes led to mitochondria enlargement and increased transmembrane potential. Collectively, these data point to a critical link between mitochondrial morphology and function and enhanced antitumor effector activity upon CD137 costimulation of T cells. Cancer Immunol Res; 6(7); 798–811. ©2018 AACR.

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Section: Experiments Human Cd8supporting

confidence: 93%

“…In this regard, a CD137-containing CAR did not increase glycolysis (19), perhaps suggesting differences between the chimeric and naturally occurring molecules.…”

Section: Discussionmentioning

confidence: 88%

Section: Discussionmentioning

confidence: 92%

Section: Introductionmentioning

confidence: 99%

See 2 more Smart Citations

Mitochondrial Morphological and Functional Reprogramming Following CD137 (4-1BB) Costimulation

Teijeira

Labiano

Garasa

et al. 2018

Cancer Immunology Research

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“…Using mRNA electroporation, Kawalekar et al (2016) demonstrated that the enhanced survival of 41BBζ CAR T cells is associated with an increased frequency of CD8+ T CM cells, while CD28ζ CAR T cells exhibited effector memory differentiation (T EM ), leading to limited persistence. (Kawalekar et al 2016).…”

Section: How To Improve Car T-cell Efficacy and Increase Access To Pementioning

confidence: 99%

Recent advances in T‐cell immunotherapy for haematological malignancies

et al. 2016

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In vitro discoveries have paved the way for bench-to-bedside translation in adoptive T cell immunotherapy, resulting in remarkable clinical responses in a variety of haematological malignancies. Adoptively transferred T cells genetically modified to express CD19 CARs have shown great promise, although many unanswered questions regarding how to optimize T-cell therapies for both safety and efficacy remain. Similarly, T cells that recognize viral or tumour antigens though their native receptors have produced encouraging clinical responses. Honing manufacturing processes will increase the availability of T-cell products, while combining T-cell therapies has the ability to increase complete response rates. Lastly, innovative mechanisms to control these therapies may improve safety profiles while genome editing offers the prospect of modulating T-cell function. This review will focus on recent advances in T-cell immunotherapy, highlighting both clinical and pre-clinical advances, as well as exploring what the future holds.

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Metabolic dialogues: regulators of chimeric antigen receptor T cell function in the tumor microenvironment

Moraly,

Kondo,

Benzaoui

et al. 2024

Molecular Oncology

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Tumor‐infiltrating lymphocytes (TILs) and chimeric antigen receptor (CAR) T cells have demonstrated remarkable success in the treatment of relapsed/refractory melanoma and hematological malignancies, respectively. These treatments have marked a pivotal shift in cancer management. However, as “living drugs,” their effectiveness is dependent on their ability to proliferate and persist in patients. Recent studies indicate that the mechanisms regulating these crucial functions, as well as the T cell's differentiation state, are conditioned by metabolic shifts and the distinct utilization of metabolic pathways. These metabolic shifts, conditioned by nutrient availability as well as cell surface expression of metabolite transporters, are coupled to signaling pathways and the epigenetic landscape of the cell, modulating transcriptional, translational, and post‐translational profiles. In this review, we discuss the processes underlying the metabolic remodeling of activated T cells, the impact of a tumor metabolic environment on T cell function, and potential metabolic‐based strategies to enhance T cell immunotherapy.

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Distinct Signaling of Coreceptors Regulates Specific Metabolism Pathways and Impacts Memory Development in CAR T Cells

Cited by 936 publications

References 53 publications

Mitochondrial Morphological and Functional Reprogramming Following CD137 (4-1BB) Costimulation

Mitochondrial Morphological and Functional Reprogramming Following CD137 (4-1BB) Costimulation

Recent advances in T‐cell immunotherapy for haematological malignancies

Metabolic dialogues: regulators of chimeric antigen receptor T cell function in the tumor microenvironment

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