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Modulating immunometabolism of tumor specific mouse and human lymphocytes to enhance T cell based therapy for cancer
  1. Madhusudhanan Sukumar1,
  2. Jie Liu2,
  3. Shashank J Patel3,
  4. Christopher A Klebanoff1,
  5. Gautam Mehta2,
  6. Rahul Roychoudhuri1,
  7. Joseph Crompton1,
  8. David Clever1,
  9. Luca Gattinoni4,
  10. Pawel Muranski5,
  11. Toren Finkel5 and
  12. Nicholas Restifo1
  1. Aff1 grid.48336.3a0000000419368075Center for Cancer ResearchNCI/NIH Bethesda MD USA
  2. Aff2 grid.48336.3a0000000419368075National Institutes of Health Rockville MD USA
  3. Aff3 grid.48336.3a0000000419368075Center for Cancer ResearchNCI/NIH Rockville MD USA
  4. Aff4 grid.48336.3a0000000419368075Experimental Transplantation and Immunology BranchNCI/NIH Bethesda MD USA
  5. Aff5 grid.94365.3d0000000122975165NIH Bethesda MD USA

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Meeting abstracts

Tumor cells and tumor infiltrating lymphocytes (TIL) competes for glucose and other metabolites within the tumor microenvironment for their survival. Glucose consumption by tumors metabolically restricts T cell's ability to produce effector cytokines and therefore approaches to improve the overall metabolic fitness of TIL may improve tumor regression in cancer patients. Long-term survival and anti-tumor immunity critically depends on their metabolic fitness but approaches to select metabolically robust T cells for adoptive immunotherapy remains less clear. Here we introduce a simple and clinically translatable method using a lipophilic cationic dye (tetramethylrhodamine methyl ester-TMRM) to identify and isolate metabolically-robust T cells based on mitochondrial membrane-potential (∆Ψm). Cells with lower membrane-potential (low-∆Ψm) had a molecular profile characteristic of memory precursors and displayed an enhanced ability to enter the memory pool as compared to cells displaying higher mitochondrial potential (high-∆Ψm) characteristic of short-lived effectors. Interestingly, we also found that multiple distinct negative inhibitory receptors such as programmed death-1 (PD-1), cytotoxic T-lymphocyte-associated protein 4 (CTLA-4), B- and T-lymphocyte attenuator (BTLA), Lymphocyte-activation gene 3 (LAG-3) and T cell immunoglobulin mucin receptor 3 (TIM-3) were enriched in the high-∆Ψm subset compared to the low-∆Ψm subset. Comprehensive metabolomic and gene expression profiling demonstrated global features of metabolic fitness in low ∆Ψm sorted CD8+ T cells—including reduced glycolysis, enhanced fatty-acid oxidation and robust spare respiratory capacity. Transfer of low-∆Ψm T cells was associated with superior long-term in vivo persistence as evidenced by 100 fold increase in the frequency of T cells 300 days after adoptive transfer, augmented autoimmunity and an enhanced capacity to eradicate established cancer compared with high-∆Ψm cells. High-∆Ψm T cells exhibited elevated ROS levels, increased effector cytokines and had up-regulation of genes involved in DNA replication, DNA repair and cell-cycle arrest genes compared to low-∆Ψm T cells. Surprisingly, use of Ψm to enrich for cells with superior metabolic features was observed within central-memory (TCM) and effector (Tc17, Th1, Th17) T cells as well as long-term hematopoietic stem cells (LT-HSC). Finally, we also demonstrate that mitochondrial membrane potential based sorting can identify CD45RO- CCR7+ human CD8+ T cells. These findings demonstrate that metabolic-sorting serves as a complementary strategy to the use of conventional cell surface markers for identifying cells with the capacity for long-term survival and ongoing effector function after adoptive-transfer. This novel metabolism-based approach may be broadly applicable to therapies involving transfer of hematopoietic stem cells or lymphocytes for treatment of viral-associated illnesses and advanced cancer.