Cystathionine‐gamma‐lyase overexpression in T cells enhances antitumor effect independently of cysteine autonomy

Abstract

T 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.

Emerging roles of cystathionine β-synthase in various forms of cancer

“…CBS knockout mice have fewer Tregs, and the reduction of Tregs cells is linked to immune cell infiltration and higher autoantibody production [ 211 , 212 ]. Elevation of intracellular H 2 S levels in T cells (achieved by CSE overexpression) was recently shown to enhance the antitumor effect of these cells in various model systems in vivo : importantly, administration of CSE-overexpressing CD8 + T cells to melanoma-bearing mice suppressed tumor growth and improved survival to a greater extent than infusion of wild-type CD8 + T cells [ 213 ]. Interestingly, this effect was not attributed to increased proliferation or higher antitumor cytotoxicity of these T cells, but likely to be related to an altered metabolic milieu of these cells [ 213 ].…”

The interaction of disulfiram and H2S metabolism in inhibition of aldehyde dehydrogenase activity and liver cancer cell growth

“…We previously reported that CSE expression was reduced in drug resistant liver cancer cells and supply of exogenous H2S could reverse drug resistance in these cells 81 . Other studies also found that overexpression of CSE in T cells significantly inhibited tumour growth in a mouse model of adoptive cell transfer, while silencing CSE gene transcription via FOXC1-mediated DNMT3B expression and DNA hyper-methylation promoted hepatocellular carcinoma survival 102,103 . This evidence demonstrated a key role of CSE/H2S system in regulating cancer growth and drug resistance possibly by targeting at ALDH.…”

Sulfurtransferases and Cystathionine Beta-Synthase Expression in Different Human Leukemia Cell Lines

“…T cells lack efficient transport of L-cysteine and are highly dependent on the extracellular availability of cystine imported through the cystine/glutamate antiporter xCT, which is expressed only after cell activation. Furthermore, T cells can import L-cysteine provided by antigen-presenting cells (macrophages, dendritic cells) through their ASC neutral amino acid transporter or thioredoxin-mediated reduction of cystine to L-cysteine [ 36 ]. T cell activation depends on hydrogen sulfide (H 2 S) signaling.…”