Cystathionine‐gamma‐lyase overexpression in T cells enhances antitumor effect independently of cysteine autonomy
Copyright policy )Cystathionine‐gamma‐lyase overexpression in T cells enhances antitumor effect independently of cysteine autonomy
AbstractT cells could be engineered to overcome the aberrant metabolic milieu of solid tumors and tip the balance in favor of a long‐lasting clinical response. Here, we explored the therapeutic potential of stably overexpressing cystathionine‐gamma‐lyase (CTH, CSE, or cystathionase), a pivotal enzyme of the transsulfuration pathway, in antitumor CD8+ T cells with the initial aim to boost intrinsic cysteine metabolism. Using a mouse model of adoptive cell transfer (ACT), we found that CTH‐expressing T cells showed a superior control of tumor growth compared to control T cells. However, contrary to our hypothesis, this effect was not associated with increased T cell expansion in vivo or proliferation rescue in the absence of cysteine/cystine in vitro. Rather than impacting methionine or cysteine, ACT with CTH overexpression unexpectedly reduced glycine, serine, and proline concentration within the tumor interstitial fluid. Interestingly, in vitro tumor cell growth was mostly impacted by the combination of serine/proline or serine/glycine deprivation. These results suggest that metabolic gene engineering of T cells could be further investigated to locally modulate amino acid availability within the tumor environment while avoiding systemic toxicity.
- Université de Nantes France
- Nantes Université France
- University of Lausanne Switzerland
- XENOTHERA France
- University of Nantes France
MESH: Cystathionine gamma-Lyase / metabolism, [SDV]Life Sciences [q-bio], MESH: Extracellular Fluid / metabolism, CD8-Positive T-Lymphocytes, Inbred C57BL, Mice, MESH: Cell Engineering, Methionine, MESH: Glycine / metabolism, MESH: Methionine / metabolism, MESH: Models, Serine, Tumor Microenvironment, MESH: Animals, cysteine, Cell Engineering, Ovarian Neoplasms, Tumor, MESH: Serine / metabolism, MESH: CD8-Positive T-Lymphocytes / metabolism, Adoptive Transfer, MESH: Ovarian Neoplasms / therapy, MESH: Proline / metabolism, Models, Animal, Female, amino acid, 570, Proline, Glycine, 610, MESH: Cysteine / biosynthesis, MESH: Cell Proliferation, Cell Line, Tumor, Animals, MESH: Tumor Microenvironment / immunology, Cysteine, MESH: Mice, adoptive cell transfer, Cell Proliferation, Animal, Cystathionine gamma-Lyase, T cell, Extracellular Fluid, Original Articles, MESH: Cell Line, Mice, Inbred C57BL, Adoptive Transfer/methods; Animals; CD8-Positive T-Lymphocytes/metabolism; Cell Engineering; Cell Line, Tumor; Cell Proliferation; Cystathionine gamma-Lyase/metabolism; Cysteine/biosynthesis; Extracellular Fluid/metabolism; Female; Glycine/metabolism; Methionine/metabolism; Mice; Mice, Inbred C57BL; Models, Animal; Ovarian Neoplasms/therapy; Proline/metabolism; Serine/metabolism; Tumor Microenvironment/immunology; T cell; adoptive cell transfer; amino acid; cysteine; metabolism, MESH: Adoptive Transfer / methods, metabolism, MESH: Female
MESH: Cystathionine gamma-Lyase / metabolism, [SDV]Life Sciences [q-bio], MESH: Extracellular Fluid / metabolism, CD8-Positive T-Lymphocytes, Inbred C57BL, Mice, MESH: Cell Engineering, Methionine, MESH: Glycine / metabolism, MESH: Methionine / metabolism, MESH: Models, Serine, Tumor Microenvironment, MESH: Animals, cysteine, Cell Engineering, Ovarian Neoplasms, Tumor, MESH: Serine / metabolism, MESH: CD8-Positive T-Lymphocytes / metabolism, Adoptive Transfer, MESH: Ovarian Neoplasms / therapy, MESH: Proline / metabolism, Models, Animal, Female, amino acid, 570, Proline, Glycine, 610, MESH: Cysteine / biosynthesis, MESH: Cell Proliferation, Cell Line, Tumor, Animals, MESH: Tumor Microenvironment / immunology, Cysteine, MESH: Mice, adoptive cell transfer, Cell Proliferation, Animal, Cystathionine gamma-Lyase, T cell, Extracellular Fluid, Original Articles, MESH: Cell Line, Mice, Inbred C57BL, Adoptive Transfer/methods; Animals; CD8-Positive T-Lymphocytes/metabolism; Cell Engineering; Cell Line, Tumor; Cell Proliferation; Cystathionine gamma-Lyase/metabolism; Cysteine/biosynthesis; Extracellular Fluid/metabolism; Female; Glycine/metabolism; Methionine/metabolism; Mice; Mice, Inbred C57BL; Models, Animal; Ovarian Neoplasms/therapy; Proline/metabolism; Serine/metabolism; Tumor Microenvironment/immunology; T cell; adoptive cell transfer; amino acid; cysteine; metabolism, MESH: Adoptive Transfer / methods, metabolism, MESH: Female
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