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l-Arginine depletion blunts antitumor T-cell responses by inducing myeloid-derived suppressor cells
Matthew Fletcher1, Maria E Ramirez1, Rosa A Sierra1
1Stanley S. Scott Cancer Center, Louisiana State University Health Sciences Center, New Orleans, Louisiana.
Abstract:
Enzymatic depletion of the nonessential amino acid l-Arginine (l-Arg) in patients with cancer by the administration of a pegylated form of the catabolic enzyme arginase I (peg-Arg I) has shown some promise as a therapeutic approach. However, l-Arg deprivation also suppresses T-cell responses in tumors. In this study, we sought to reconcile these observations by conducting a detailed analysis of the effects of peg-Arg I on normal T cells. Strikingly, we found that peg-Arg I blocked proliferation and cell-cycle progression in normal activated T cells without triggering apoptosis or blunting T-cell activation. These effects were associated with an inhibition of aerobic glycolysis in activated T cells, but not with significant alterations in mitochondrial oxidative respiration, which thereby regulated survival of T cells exposed to peg-Arg I. Further mechanistic investigations showed that the addition of citrulline, a metabolic precursor for l-Arg, rescued the antiproliferative effects of peg-Arg I on T cells in vitro. Moreover, serum levels of citrulline increased after in vivo administration of peg-Arg I. In support of the hypothesis that peg-Arg I acted indirectly to block T-cell responses in vivo, peg-Arg I inhibited T-cell proliferation in mice by inducing accumulation of myeloid-derived suppressor cells (MDSC). MDSC induction by peg-Arg I occurred through the general control nonrepressed-2 eIF2α kinase. Moreover, we found that peg-Arg I enhanced the growth of tumors in mice in a manner that correlated with higher MDSC numbers. Taken together, our results highlight the risks of the l-Arg-depleting therapy for cancer treatment and suggest a need for cotargeting MDSC in such therapeutic settings.
Insights
Pegylated arginase I (peg-Arg I) depletes l-Arginine, inhibiting T-cell proliferation and enhancing tumor growth by increasing myeloid-derived suppressor cells (MDSC). Cotargeting MDSC is crucial for l-Arg-depleting cancer therapies.
Area of Science:
- Immunology
- Metabolic pathways
- Cancer therapy
Background:
- Enzymatic depletion of l-Arginine (l-Arg) using pegylated arginase I (peg-Arg I) is a potential cancer therapy.
- However, l-Arg deprivation can suppress anti-tumor T-cell responses.
- The precise impact of peg-Arg I on normal T cells requires further investigation.
Purpose of the Study:
- To analyze the effects of peg-Arg I on normal T cells.
- To elucidate the mechanisms underlying peg-Arg I's impact on T-cell function and survival.
- To evaluate the in vivo consequences of peg-Arg I administration in a cancer model.
Main Methods:
- Treatment of activated normal T cells with peg-Arg I in vitro.
- Assessment of T-cell proliferation, cell-cycle progression, activation, apoptosis, and metabolic profiles (aerobic glycolysis, mitochondrial respiration).
- In vivo studies in mice involving peg-Arg I administration, monitoring of T-cell proliferation, MDSC accumulation, and tumor growth.
Main Results:
- Peg-Arg I blocked proliferation and cell-cycle progression of normal activated T cells without inducing apoptosis or blunting activation.
- Inhibition of aerobic glycolysis, but not mitochondrial respiration, was observed in T cells treated with peg-Arg I.
- Citrulline supplementation rescued T-cell proliferation, and serum citrulline levels increased post-peg-Arg I administration.
- Peg-Arg I induced MDSC accumulation via the general control nonrepressed-2 eIF2α kinase, inhibiting T-cell proliferation in vivo.
- Peg-Arg I enhanced tumor growth in mice, correlating with increased MDSC numbers.
Conclusions:
- Peg-Arg I exerts antiproliferative effects on T cells by inhibiting aerobic glycolysis and is rescued by citrulline.
- Peg-Arg I indirectly suppresses T-cell responses in vivo through MDSC induction.
- The observed enhancement of tumor growth suggests potential risks associated with l-Arg-depleting therapy.
- Cotargeting MDSC is recommended for optimizing l-Arg-depleting cancer treatment strategies.
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