Tumor cell–derived spermidine promotes a protumorigenic immune microenvironment in glioblastoma via CD8+ T cell inhibition
The glioblastoma (GBM) microenvironment is enriched in immunosuppressive factors that potently interfere with the function of cytotoxic T lymphocytes. Cancer cells can directly affect the immune system, but the mechanisms driving these interactions are not completely clear. Here, we demonstrate that the polyamine metabolite spermidine (SPD) was elevated in the GBM tumor microenvironment. Exogenous administration of SPD drove tumor aggressiveness in an immune-dependent manner in preclinical mouse models via reduction of CD8+ T cell frequency and reduced cytotoxic function. Knockdown of ornithine decarboxylase, the rate-limiting enzyme in SPD synthesis, did not affect cancer cell growth in vitro but did result in extended survival. Furthermore, patients with GBM with a more favorable outcome had a significant reduction in SPD compared with patients with a poor prognosis. Our results demonstrate that SPD functions as a cancer cell-derived metabolite that drives tumor progression by reducing CD8+ T cell numbers and function.
Authors
- Justin Durla Lathia (ORCID: https://orcid.org/0000-0003-3168-7290)
- Josephine Volovetz (ORCID: https://orcid.org/0000-0003-4812-809X)
- Mary McGraw (ORCID: https://orcid.org/0000-0001-5267-489X)
- Kristen Kay (ORCID: https://orcid.org/0000-0002-4459-6454)
- Jennifer S. Yu
- Vinod K. Narayana (ORCID: https://orcid.org/0000-0003-3980-7496)
- Zeneng Wang (ORCID: https://orcid.org/0000-0002-6455-8228)
- James Richard Whittle (ORCID: https://orcid.org/0000-0002-4740-2037)
- Sadie Johnson (ORCID: https://orcid.org/0000-0001-5250-9835)
- Stanley L. Hazen (ORCID: https://orcid.org/0000-0001-7124-6639)
- Sabrina Wang (ORCID: https://orcid.org/0000-0002-5541-7327)
- Daniel J. Silver (ORCID: https://orcid.org/0000-0002-7085-2626)
- Defne Bayık (ORCID: https://orcid.org/0000-0002-4740-8869)
- Emily Wesley
- J. Mark Brown (ORCID: https://orcid.org/0000-0003-2708-7487)
- Matthew M. Grabowski (ORCID: https://orcid.org/0000-0001-8550-0124)
- Juyeun Lee (ORCID: https://orcid.org/0000-0001-8276-5020)
- Lutz Freytag (ORCID: https://orcid.org/0009-0009-9256-6127)
- Sahil Dayal (ORCID: https://orcid.org/0000-0002-2584-5056)
- Sarah A. Best (ORCID: https://orcid.org/0000-0002-4232-9432)
- Ellen S. Hong (ORCID: https://orcid.org/0000-0002-5299-4217)
- Ofer Reizes (ORCID: https://orcid.org/0000-0003-0075-6871)
- Saskia Freytag (ORCID: https://orcid.org/0000-0002-2185-7068)
- Julia L Beilis
- Tianyao Lu
- Sofia Mitchell
Institutions
- Cleveland Clinic (US)
- The University of Melbourne (AU)
- Walter and Eliza Hall Institute of Medical Research (AU)
- Peter MacCallum Cancer Centre (AU)
- Cleveland Clinic Lerner College of Medicine (US)
- Department of Medical Sciences (RU)
- Cellular Research (United States) (US)
- Sylvester Comprehensive Cancer Center (US)
- Melbourne Genomics Health Alliance (AU)
- Case Comprehensive Cancer Center
- Case Western Reserve University (US)
Publication Details
- Journal
- Journal of Clinical Investigation
- Published
- 2024-11-19
- DOI
- https://doi.org/10.1172/jci177824
- Citations
- 15
- Primary Topic
- Polyamine Metabolism and Applications
- Type
- article
- Field-Weighted Citation Impact
- 3.51
Funders
- Northwestern University
- Cleveland Clinic
- University of Pittsburgh
- Victorian Cancer Agency
- Case Comprehensive Cancer Center, Case Western Reserve University
- Quest Diagnostics
- Perpetual
- National Institutes of Health
- National Health and Medical Research Council
- Cancer Council Victoria