Manipulating the Metabolism to Improve the Efficacy of CAR T-Cell Immunotherapy

Pellegrino, Marsha; Bufalo, Francesca Del; Angelis, Biagio De; Quintarelli, Concetta; Caruana, Ignazio; Billy, Emmanuel de

doi:10.3390/cells10010014

Cited by 37 publications

(36 citation statements)

References 126 publications

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“…T cell metabolism can be modulated ex vivo using interleukin (IL)-7 and IL-15 that can promote memory T cell generation thanks to their ability to increase mitochondrial biogenesis and FAO [ 101 , 102 ]. CAR T cells could be engineered to modulate immune checkpoint inhibitor response and to improve TME modulation [ 103 ].…”

Section: Discussionmentioning

confidence: 99%

Altered Metabolism in Glioblastoma: Myeloid-Derived Suppressor Cell (MDSC) Fitness and Tumor-Infiltrating Lymphocyte (TIL) Dysfunction

Ianni

Musio

Pellegatta

2021

IJMS

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The metabolism of glioblastoma (GBM), the most aggressive and lethal primary brain tumor, is flexible and adaptable to different adverse conditions, such as nutrient deprivation. Beyond glycolysis, altered lipid metabolism is implicated in GBM progression. Indeed, metabolic subtypes were recently identified based on divergent glucose and lipid metabolism. GBM is also characterized by an immunosuppressive microenvironment in which myeloid-derived suppressor cells (MDSCs) are a powerful ally of tumor cells. Increasing evidence supports the interconnection between GBM and MDSC metabolic pathways. GBM cells exert a crucial contribution to MDSC recruitment and maturation within the tumor microenvironment, where the needs of tumor-infiltrating lymphocytes (TILs) with antitumor function are completely neglected. In this review, we will discuss the unique or alternative source of energy exploited by GBM and MDSCs, exploring how deprivation of specific nutrients and accumulation of toxic byproducts can induce T-cell dysfunction. Understanding the metabolic programs of these cell components and how they impact fitness or dysfunction will be useful to improve treatment modalities, including immunotherapeutic strategies.

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Section: Discussionmentioning

confidence: 99%

Altered Metabolism in Glioblastoma: Myeloid-Derived Suppressor Cell (MDSC) Fitness and Tumor-Infiltrating Lymphocyte (TIL) Dysfunction

Ianni

Musio

Pellegatta

2021

IJMS

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“…How this may be translated into new therapies remains uncertain, but targeting metabolism may be incorporated into cell-based therapies involving T cells. For example, chimeric antigen receptor (CAR) expressing T cells have become an effective approach for treating some cancers, and advances have been made to improve the metabolic fitness and efficacy of CAR T cells [ 66 ]. This may provide a framework for developing new strategies in treating diseases, including autoimmune disorders, focused on regulating T cell metabolism and providing optimal immunity.…”

Section: Discussionmentioning

confidence: 99%

Roles for Selenoprotein I and Ethanolamine Phospholipid Synthesis in T Cell Activation

Martinez-Rodriguez

Hoffmann

2021

IJMS

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The selenoprotein family includes 25 members, many of which are antioxidant or redox regulating enzymes. A unique member of this family is Selenoprotein I (SELENOI), which does not catalyze redox reactions, but instead is an ethanolamine phosphotransferase (Ept). In fact, the characteristic selenocysteine residue that defines selenoproteins lies far outside of the catalytic domain of SELENOI. Furthermore, data using recombinant SELENOI lacking the selenocysteine residue have suggested that the selenocysteine amino acid is not directly involved in the Ept reaction. SELENOI is involved in two different pathways for the synthesis of phosphatidylethanolamine (PE) and plasmenyl PE, which are constituents of cellular membranes. Ethanolamine phospholipid synthesis has emerged as an important process for metabolic reprogramming that occurs in pluripotent stem cells and proliferating tumor cells, and this review discusses roles for upregulation of SELENOI during T cell activation, proliferation, and differentiation. SELENOI deficiency lowers but does not completely diminish de novo synthesis of PE and plasmenyl PE during T cell activation. Interestingly, metabolic reprogramming in activated SELENOI deficient T cells is impaired and this reduces proliferative capacity while favoring tolerogenic to pathogenic phenotypes that arise from differentiation. The implications of these findings are discussed related to vaccine responses, autoimmunity, and cell-based therapeutic approaches.

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“…Functionally, MEK inhibition administered with vaccination against known antigens (gp100 in melanoma, HPV16E7 in cervical carcinoma model) in murine cancer models successfully increased numbers of circulating CD8+ T-cells, reduced tumor burden, and improved survival rates ( 175 ). Indeed, manipulations of T-cell metabolism may help to improve the efficacy of T-cell-based immunotherapies ( 176 ).…”

Section: Immune Cell Programming and Reprogrammingmentioning

confidence: 99%

Cell Fate Reprogramming in the Era of Cancer Immunotherapy

et al. 2021

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Advances in understanding how cancer cells interact with the immune system allowed the development of immunotherapeutic strategies, harnessing patients’ immune system to fight cancer. Dendritic cell-based vaccines are being explored to reactivate anti-tumor adaptive immunity. Immune checkpoint inhibitors and chimeric antigen receptor T-cells (CAR T) were however the main approaches that catapulted the therapeutic success of immunotherapy. Despite their success across a broad range of human cancers, many challenges remain for basic understanding and clinical progress as only a minority of patients benefit from immunotherapy. In addition, cellular immunotherapies face important limitations imposed by the availability and quality of immune cells isolated from donors. Cell fate reprogramming is offering interesting alternatives to meet these challenges. Induced pluripotent stem cell (iPSC) technology not only enables studying immune cell specification but also serves as a platform for the differentiation of a myriad of clinically useful immune cells including T-cells, NK cells, or monocytes at scale. Moreover, the utilization of iPSCs allows introduction of genetic modifications and generation of T/NK cells with enhanced anti-tumor properties. Immune cells, such as macrophages and dendritic cells, can also be generated by direct cellular reprogramming employing lineage-specific master regulators bypassing the pluripotent stage. Thus, the cellular reprogramming toolbox is now providing the means to address the potential of patient-tailored immune cell types for cancer immunotherapy. In parallel, development of viral vectors for gene delivery has opened the door for in vivo reprogramming in regenerative medicine, an elegant strategy circumventing the current limitations of in vitro cell manipulation. An analogous paradigm has been recently developed in cancer immunotherapy by the generation of CAR T-cells in vivo. These new ideas on endogenous reprogramming, cross-fertilized from the fields of regenerative medicine and gene therapy, are opening exciting avenues for direct modulation of immune or tumor cells in situ, widening our strategies to remove cancer immunotherapy roadblocks. Here, we review current strategies for cancer immunotherapy, summarize technologies for generation of immune cells by cell fate reprogramming as well as highlight the future potential of inducing these unique cell identities in vivo, providing new and exciting tools for the fast-paced field of cancer immunotherapy.

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Manipulating the Metabolism to Improve the Efficacy of CAR T-Cell Immunotherapy

Cited by 37 publications

References 126 publications

Altered Metabolism in Glioblastoma: Myeloid-Derived Suppressor Cell (MDSC) Fitness and Tumor-Infiltrating Lymphocyte (TIL) Dysfunction

Altered Metabolism in Glioblastoma: Myeloid-Derived Suppressor Cell (MDSC) Fitness and Tumor-Infiltrating Lymphocyte (TIL) Dysfunction

Roles for Selenoprotein I and Ethanolamine Phospholipid Synthesis in T Cell Activation

Cell Fate Reprogramming in the Era of Cancer Immunotherapy

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