Supplementation ofl-arginine boosts the therapeutic efficacy of anticancer chemoimmunotherapy

Myeloid-derived suppressor cells (MDSCs) play a crucial role in immunosuppression in tumor-bearing hosts. MDSCs express arginase-I and indoleamine 2,3-dioxygenase; they suppress T-cell function by reducing the levels ofl-arginine andl-tryptophan, respectively. We examined the anticancer effects of supplementation of these amino acids in CT26 colon carcinoma-bearing mice. Oral supplementation ofl-arginine orl-tryptophan (30 mg/mouse) did not affect tumor growth, whereas oral supplementation ofd-arginine was lethal. Supplementation ofl-arginine showed a tendency to augment the efficacy of cyclophosphamide (CP). CP reduced the proportions of granulocytic MDSCs and increased the proportions of monocytic MDSCs in the spleen and tumor tissues of CT26-bearing mice.l-Arginine supplementation alone did not affect the MDSC subsets. CP treatment tended to reduce the plasma levels ofl-arginine in CT26-bearing mice and significantly increased the number of tumor-infiltrating CD8(+)T cells. In addition,l-arginine supplementation significantly increased the proportions of tumor peptide-specific CD8(+)T cells in draining lymph nodes. Importantly, additional supplementation ofl-arginine significantly increased the number of cured mice that were treated with CP and anti-PD-1 antibody. Totally,l-arginine supplementation shows promise for boosting the therapeutic efficacy of chemoimmunotherapy.