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Poster Presentations
09. Cell Therapy in Solid Tumors
P09.01 Adapting immune cells to the hypoglycemic tumor microenvironment by solute carrier 2a1 (Slc2a1/GLUT1) overexpression
  1. ME Kirmaier1,2,3,
  2. BL Cadilha4,
  3. A Hadzic1,2,3,
  4. W Schmitz5,
  5. MR Benmebarek4,
  6. D Briukhovetska4,
  7. S Michaelides4,
  8. V Buschinger6,
  9. B Tast1,7,
  10. CH Bönigk4,
  11. S Oganesian1,2,3,
  12. L Vona1,2,3,
  13. A Tischmacher1,
  14. V Heissmeyer8,
  15. M Vaeth9,
  16. VR Buchholz6,
  17. M Eilers5,
  18. M von Bergwelt-Baildon1,3,
  19. M Subklewe1,7,
  20. S Kobold4 and
  21. S Theurich1,2,3
  1. 1Department of Medicine III, LMU Klinikum, Munich, Germany
  2. 2Cancer and Immunometabolism Research Group, Gene Center, LMU Munich, Munich, Germany
  3. 3German Cancer Consortium (DKTK), Partner site Munich, Heidelberg, Germany
  4. 4Department of Medicine IV, Division of Clinical Pharmacology, LMU Munich, Munich, Germany
  5. 5Department of Biochemistry and Molecular Biology, Biocenter, JMU Würzburg, Würzburg, Germany
  6. 6Institute for Medical Microbiology, Immunology and Hygiene, TU Munich, Munich, Germany
  7. 7Translational Cancer Immunology Research Group, Gene Center, LMU Munich, Munich, Germany
  8. 8Institute for Immunology, LMU Munich, Biomedical Center Munich, Munich, Germany, Munich, Germany
  9. 9Institute of Systems Immunology, Max Planck Research Group, JMU Würzburg, Würzburg, Germany, Würzburg, Germany

Abstract

Background In recent years, T cell-based immunotherapies have shown promising results in hematologic malignancies. However, these strategies seem to be limited in solid cancers, posing more complex challenges including a hostile TME with nutrient deprivation and tissue hypoxia [1]. Additionally, metabolic reprogramming has been identified as a crucial factor for proper cytotoxic T-cell functions upon their activation. Such energy demands are answered by the upregulation of glycolysis, oxidative phosphorylation, and upregulation of nutrient transporters represented by SLCs [2,3]. Within the TME, tumor and immune cells compete for nutrients and shape a distinct metabolic milieu, resulting in an ineffective effector function [4]. Herein, we aim to metabolically engineer T cells to improve their fitness in the glucose-deprived TME and optimize ACT.

Materials and Methods We retrovirally overexpressed the glucose transporter Slc2a1/GLUT1 in murine CD8+ T cells (CD8+Slc2a1). To assess T-cell fitness we conducted experiments in physiologic (5mM) and hypoglycemic (0.5mM) media conditions. CellTraceTM-based proliferation experiments and killing assays in the OT1-OVA model are used to examine differences to MOCK in functionality and were analyzed via flow cytometry and microscopy, respectively. Furthermore, Seahorse analyses, bulk RNA-Seq, and metabolomic analyses were performed to examine the mechanical background. Murine in vivo studies are performed to approach the translatability of this system into living organisms.

Results CD8+Slc2a1 cells possessed a higher proliferative capacity in all conditions tested but most prominently in hypoglycemic (0.5mM) media. This better functional activity of CD8+Slc2a1 was also translated to higher killing rates in coculture assays with tumor cells, especially in low-glucose environments. Metabolic flux analyses and multi-omics suggested greater metabolic activity of CD8+Slc2a1 and revealed higher ROS production and upregulation of correlating anti-oxidative pathways, especially the pentose-phosphate pathway. Preliminary in vivo studies support the in vitro killing in a syngeneic tumor model. Furthermore, signs of altered memory formation were visible, expressed in a higher proportion of effector memory cells.

Conclusions Our data point to the role of GLUT1 overexpression in T cells for improved cytotoxic activity, proliferation, and long-term persistence. Therefore, combinatorial approaches with GLUT1 overexpression could serve as a potential approach to increase efficacy in ACT against solid cancer. We also identified GLUT1-dependent reprogramming in CD8+Slc2a1 cells which is further investigated in ongoing studies. Additionally, we are evaluating the potential risk of this approach to neoplastic formation.

References

  1. Treating hematological malignancies with cell therapy: where are we now? Landoni E, Savoldo B.; Expert Opin Biol Ther. 2018.

  2. Anticancer targets in the glycolytic metabolism of tumors: a comprehensive review; Paolo E. Porporato et al. Frontiers in Pharmacology 2011.

  3. Glucose Metabolism on Tumor Plasticity, Diagnosis, and Treatment; Lin Xiaoping et al. Frontiers in Oncology 2020

  4. Fighting in a wasteland: deleterious metabolites and antitumor immunity. Watson MJ, Delgoffe GM. J Clin Invest. 2022.

References M.E. Kirmaier: None. B.L. Cadilha: None. A. Hadzic: None. W. Schmitz: None. M.R. Benmebarek: None. D. Briukhovetska: None. S. Michaelides: None. V. Buschinger: None. B. Tast: None. C.H. Bönigk: None. S. Oganesian: None. L. Vona: None. A. Tischmacher: None. V. Heissmeyer: None. M. Vaeth: None. V.R. Buchholz: None. M. Eilers: None. M. von Bergwelt-Baildon: None. M. Subklewe: None. S. Kobold: None. S. Theurich: None.

http://creativecommons.org/licenses/by-nc/4.0/

This is an open access article distributed in accordance with the Creative Commons Attribution Non Commercial (CC BY-NC 4.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited, appropriate credit is given, any changes made indicated, and the use is non-commercial. See http://creativecommons.org/licenses/by-nc/4.0/.

https://doi.org/10.1136/jitc-2024-ITOC10.45

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