CD28 costimulation drives tumor-infiltrating T cell glycolysis to promote inflammation

Metabolic reprogramming dictates the fate and function of stimulated T cells, yet these pathways can be suppressed in T cells in tumor microenvironments. We previously showed that glycolytic and mitochondrial adaptations directly contribute to reducing the effector function of renal cell carcinoma (RCC) CD8+ tumor-infiltrating lymphocytes (TILs). Here we define the role of these metabolic pathways in the activation and effector functions of CD8+ RCC TILs. CD28 costimulation plays a key role in augmenting T cell activation and metabolism, and is antagonized by the inhibitory and checkpoint immunotherapy receptors CTLA4 and PD-1. While RCC CD8+ TILs were activated at a low level when stimulated through the T cell receptor alone, addition of CD28 costimulation greatly enhanced activation, function, and proliferation. CD28 costimulation reprogrammed RCC CD8+ TIL metabolism with increased glycolysis and mitochondrial oxidative metabolism, possibly through upregulation of GLUT3. Mitochondria also fused to a greater degree, with higher membrane potential and overall mass. These phenotypes were dependent on glucose metabolism, as the glycolytic inhibitor 2-deoxyglucose both prevented changes to mitochondria and suppressed RCC CD8+ TIL activation and function. These data show that CD28 costimulation can restore RCC CD8+ TIL metabolism and function through rescue of T cell glycolysis that supports mitochondrial mass and activity.

[1]  J. Powell,et al.  Glutamine blockade induces divergent metabolic programs to overcome tumor immune evasion , 2019, Science.

[2]  T. Graeber,et al.  Global alteration of T-lymphocyte metabolism by PD-L1 checkpoint involves a block of de novo nucleoside phosphate synthesis , 2019, Cell Discovery.

[3]  S. Heath,et al.  PD-1 signaling affects cristae morphology and leads to mitochondrial dysfunction in human CD8+ T lymphocytes , 2019, Journal of Immunotherapy for Cancer.

[4]  T. Jenuwein,et al.  Acetate Promotes T Cell Effector Function during Glucose Restriction. , 2019, Cell reports.

[5]  L. Morel,et al.  Targeting T Cell Activation and Lupus Autoimmune Phenotypes by Inhibiting Glucose Transporters , 2019, Front. Immunol..

[6]  B. Rini,et al.  Emerging Role of Combination Immunotherapy in the First-line Treatment of Advanced Renal Cell Carcinoma: A Review , 2019, JAMA oncology.

[7]  T. Powles,et al.  Pembrolizumab plus Axitinib versus Sunitinib for Advanced Renal‐Cell Carcinoma , 2019, The New England journal of medicine.

[8]  J. Locasale,et al.  Distinct Regulation of Th17 and Th1 Cell Differentiation by Glutaminase-Dependent Metabolism , 2018, Cell.

[9]  Douglas B. Johnson,et al.  Computational Immune Monitoring Reveals Abnormal Double-Negative T Cells Present across Human Tumor Types , 2018, Cancer Immunology Research.

[10]  T. Honjo,et al.  PPAR-Induced Fatty Acid Oxidation in T Cells Increases the Number of Tumor-Reactive CD8+ T Cells and Facilitates Anti–PD-1 Therapy , 2018, Cancer Immunology Research.

[11]  G. Rabinovich,et al.  IRE1α-XBP1 controls T cell function in ovarian cancer by regulating mitochondrial activity , 2018, Nature.

[12]  Boxi Kang,et al.  Global characterization of T cells in non-small-cell lung cancer by single-cell sequencing , 2018, Nature Medicine.

[13]  C. Klein,et al.  A transcriptionally and functionally distinct PD-1+ CD8+ T cell pool with predictive potential in non-small cell lung cancer treated with PD-1 blockade , 2018, Nature Medicine.

[14]  E. Pearce,et al.  Unraveling the Complex Interplay Between T Cell Metabolism and Function. , 2018, Annual review of immunology.

[15]  T. Schumacher,et al.  T Cell Dysfunction in Cancer. , 2018, Cancer cell.

[16]  Simon C Watkins,et al.  4-1BB costimulation induces T cell mitochondrial function and biogenesis enabling cancer immunotherapeutic responses , 2018, The Journal of experimental medicine.

[17]  Bohuslav Melichar,et al.  Nivolumab plus Ipilimumab versus Sunitinib in Advanced Renal‐Cell Carcinoma , 2018, The New England journal of medicine.

[18]  H. Huthoff,et al.  Upregulation of Glucose Uptake and Hexokinase Activity of Primary Human CD4+ T Cells in Response to Infection with HIV-1 , 2018, Viruses.

[19]  Joerg M. Buescher,et al.  Mitochondrial Priming by CD28 , 2017, Cell.

[20]  G. Freeman,et al.  Enhancing CD8+ T Cell Fatty Acid Catabolism within a Metabolically Challenging Tumor Microenvironment Increases the Efficacy of Melanoma Immunotherapy. , 2017, Cancer cell.

[21]  W. Rathmell,et al.  Mitochondrial dysregulation and glycolytic insufficiency functionally impair CD8 T cells infiltrating human renal cell carcinoma. , 2017, JCI insight.

[22]  J. Rathmell,et al.  Dysfunctional T cell metabolism in the tumor microenvironment. , 2017, Cytokine & growth factor reviews.

[23]  Michael B. Stadler,et al.  An Immune Atlas of Clear Cell Renal Cell Carcinoma , 2017, Cell.

[24]  Kevin R. Moon,et al.  PHATE: A Dimensionality Reduction Method for Visualizing Trajectory Structures in High-Dimensional Biological Data , 2017 .

[25]  T. Honjo,et al.  Mitochondrial activation chemicals synergize with surface receptor PD-1 blockade for T cell-dependent antitumor activity , 2017, Proceedings of the National Academy of Sciences.

[26]  J. Sosman,et al.  PD-1/PD-L1 blockade in renal cell cancer , 2017, Expert review of clinical immunology.

[27]  Kirsten E Diggins,et al.  Characterizing cell subsets in heterogeneous tissues using marker enrichment modeling , 2016, Nature Methods.

[28]  Simon C Watkins,et al.  The Tumor Microenvironment Represses T Cell Mitochondrial Biogenesis to Drive Intratumoral T Cell Metabolic Insufficiency and Dysfunction. , 2016, Immunity.

[29]  O. Kretz,et al.  Mitochondrial Dynamics Controls T Cell Fate through Metabolic Programming , 2016, Cell.

[30]  Linda V. Sinclair,et al.  Glucose and glutamine fuel protein O-GlcNAcylation to control T cell self-renewal and malignancy , 2016, Nature Immunology.

[31]  J. Irish,et al.  High-Dimensional Analysis of Acute Myeloid Leukemia Reveals Phenotypic Changes in Persistent Cells during Induction Therapy , 2016, PloS one.

[32]  J. Sosman,et al.  Myelodysplastic Syndrome Revealed by Systems Immunology in a Melanoma Patient Undergoing Anti–PD-1 Therapy , 2016, Cancer Immunology Research.

[33]  Brian Keith,et al.  Distinct Signaling of Coreceptors Regulates Specific Metabolism Pathways and Impacts Memory Development in CAR T Cells. , 2016, Immunity.

[34]  A. Ravaud,et al.  Nivolumab versus Everolimus in Advanced Renal-Cell Carcinoma. , 2015, The New England journal of medicine.

[35]  R. Schreiber,et al.  Metabolic Competition in the Tumor Microenvironment Is a Driver of Cancer Progression , 2015, Cell.

[36]  J. Locasale,et al.  Phosphoenolpyruvate Is a Metabolic Checkpoint of Anti-tumor T Cell Responses , 2015, Cell.

[37]  J. Rathmell,et al.  T cell metabolic fitness in antitumor immunity. , 2015, Trends in immunology.

[38]  G. Freeman,et al.  PD-1 alters T-cell metabolic reprogramming by inhibiting glycolysis and promoting lipolysis and fatty acid oxidation , 2015, Nature Communications.

[39]  W. Rathmell,et al.  HIF1α and HIF2α Exert Distinct Nutrient Preferences in Renal Cells , 2014, PloS one.

[40]  Sean C. Bendall,et al.  Normalization of mass cytometry data with bead standards , 2013, Cytometry. Part A : the journal of the International Society for Analytical Cytology.

[41]  H. Baker,et al.  Murine Lupus Susceptibility Locus Sle1c2 Mediates CD4+ T Cell Activation and Maps to Estrogen-Related Receptor γ , 2012, The Journal of Immunology.

[42]  D. Green,et al.  The transcription factor Myc controls metabolic reprogramming upon T lymphocyte activation. , 2011, Immunity.

[43]  J. Rathmell,et al.  Cutting Edge: Distinct Glycolytic and Lipid Oxidative Metabolic Programs Are Essential for Effector and Regulatory CD4+ T Cell Subsets , 2011, The Journal of Immunology.

[44]  Ash A. Alizadeh,et al.  B-cell signaling networks reveal a negative prognostic human lymphoma cell subset that emerges during tumor progression , 2010, Proceedings of the National Academy of Sciences.

[45]  J. Rathmell,et al.  IL-7 Is Essential for Homeostatic Control of T Cell Metabolism In Vivo , 2010, The Journal of Immunology.

[46]  Greg M. Delgoffe,et al.  Anergic T Cells Are Metabolically Anergic1 , 2009, The Journal of Immunology.

[47]  W. Rathmell,et al.  VHL Type 2B gene mutation moderates HIF dosage in vitro and in vivo , 2009, Oncogene.

[48]  J. Rathmell,et al.  Glucose Uptake Is Limiting in T Cell Activation and Requires CD28-Mediated Akt-Dependent and Independent Pathways1 , 2008, The Journal of Immunology.

[49]  E. Boutati,et al.  Glucose transporter expression on the plasma membrane of resting and activated white blood cells , 2007, European journal of clinical investigation.

[50]  C. Thompson,et al.  The CD28 signaling pathway regulates glucose metabolism. , 2002, Immunity.