Adoptive cell therapy (ACT) is an immunotherapeutic approach that involves isolating T cells from a patient, culturing them ex vivo, then reinfusing the cells back into the patient. Although this ...strategy has shown remarkable efficacy in hematological malignancies, the solid-tumour microenvironment (TME) has presented serious challenges for therapy efficacy. Particularly, the TME has immunosuppressive signalling and presents a metabolically challenging environment that leads to T-cell suppression. T-cell metabolism is an expanding field of research with a focus on understanding its inherent link to T-cell function. Here, we review the current model of T-cell metabolism from naïve cells through effector and memory life stages, as well as updates to the model from recent literature. These models of metabolism have provided us with the tools and understanding to explore T-cell metabolic and mitochondrial insufficiency in the TME. We discuss manipulations that can be made to these mitochondrial and metabolic pathways to enhance the persistence of infused T cells, overcome the metabolically challenging TME and improve the efficacy of therapy in ACT models. Further understanding and investigation of the impact of metabolic pathways on T-cell performance could contribute to improving therapy efficacy for patients.
Metabolic programming is intricately linked to the anti-tumor properties of T cells. To study the metabolic pathways associated with increased anti-tumor T cell function, we utilized a metabolomics ...approach to characterize three different CD8
T cell subsets with varying degrees of anti-tumor activity in murine models, of which IL-22-producing Tc22 cells displayed the most robust anti-tumor activity. Tc22s demonstrated upregulation of the pantothenate/coenzyme A (CoA) pathway and a requirement for oxidative phosphorylation (OXPHOS) for differentiation. Exogenous administration of CoA reprogrammed T cells to increase OXPHOS and adopt the CD8
Tc22 phenotype independent of polarizing conditions via the transcription factors HIF-1α and the aryl hydrocarbon receptor (AhR). In murine tumor models, treatment of mice with the CoA precursor pantothenate enhanced the efficacy of anti-PDL1 antibody therapy. In patients with melanoma, pre-treatment plasma pantothenic acid levels were positively correlated with the response to anti-PD1 therapy. Collectively, our data demonstrate that pantothenate and its metabolite CoA drive T cell polarization, bioenergetics, and anti-tumor immunity.
The manipulation of T cell metabolism to enhance anti-tumor activity is an area of active investigation. Here, we report that activating the amino acid starvation response in effector CD8+ T cells ...ex vivo using the general control non-depressible 2 (GCN2) agonist halofuginone (halo) enhances oxidative metabolism and effector function. Mechanistically, we identified autophagy coupled with the CD98-mTOR axis as key downstream mediators of the phenotype induced by halo treatment. The adoptive transfer of halo-treated CD8+ T cells into tumor-bearing mice led to robust tumor control and curative responses. Halo-treated T cells synergized in vivo with a 4-1BB agonistic antibody to control tumor growth in a mouse model resistant to immunotherapy. Importantly, treatment of human CD8+ T cells with halo resulted in similar metabolic and functional reprogramming. These findings demonstrate that activating the amino acid starvation response with the GCN2 agonist halo can enhance T cell metabolism and anti-tumor activity.
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•Arginine (arg) withdrawal activates the GCN2 pathway in CD8+ T cells•Activation of GCN2 increases oxidative metabolism and effector function in CD8+ T cells•Halofuginone (halo) induces the same phenotype as arg withdrawal in CD8+ T cells•Halo enhances the efficacy of CD8+ T cells in models of adoptive cell therapy
The impact of GCN2 signaling on the function and metabolism of activated CD8+ T cells was unclear. St. Paul et al. demonstrate that activation of GCN2 in CD8+ T cells results in increased oxidative metabolism and anti-tumor activity. Targeting GCN2 can be a new avenue to enhance cancer immunotherapy.
The Curriculum of Caring for People with Developmental Disabilities provides experiential learning to improve the capacity of healthcare professionals to deliver person/family-centred care to people ...who live with intellectual and/or developmental disabilities (ID/DD). The purpose of this project was to explore the impact of the curriculum on medical students’ self-reported comfort, confidence, and competence in providing healthcare to the ID/DD population. The rationale for this study was to better understand how experiential learning (bringing people with lived experience into the medical school experience of trainees) might prepare future physicians to improve health care experiences for an underserved population.
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