Accumulation of lactic acid in the tumor microenvironment contributes to local immunosuppressive conditions that weaken anti-tumor immunity. Lactic acid exists as L- and D- optical isomers. In mammals including humans, lactate is present almost entirely as L-lactate. We hypothesized that D-lactate could have immune modulatory effects similar to L-lactate that maybe exploited for therapeutic immunosuppression, as D-lactate is slower eliminated than L-lactate. We observed that 5–40 mM of added sodium D- and L-lactate caused marked impairment of murine, and human, CD4 and CD8 T cell proliferation in vitro, with stronger effects of D-lactate than L-lactate. Neither D- nor L-lactate affected cell viability and apoptosis (measured by 7AAD and annexin V). Adding 20 mM D-lactate to CD4⁺CD25^–Foxp3^–T cells under polarizing conditions increased Foxp3⁺ induced regulatory T cell (iTreg) formation by 46.2 ±31.5% (P<0.03, n=4). L-lactate also augmented Treg induction but to a lesser degree (22.8 ±22.7%, p=0.09). To test the effects of D-lactate in vivo, we adoptively transferred 1[times]10⁶ conventional T cells, with or without 1.25[times]10⁵ Tregs, into Rag1^–/– mice, treated each group with 90 mmol/kg/d D-lactate or NaCl for 5 days, and assessed T cell proliferation and differentiation at 7 days. We found that T cell proliferation was reduced by 62.1% using D-lactate treatment (P<0.03, n=8). While Treg suppressive function was unaffected, de-novo Foxp3⁺ Treg formation was increased in D-lactate (14.9 ±3.4%) vs. NaCl (10.6 ±2.3%) treated animals (P<0.01, n=8). Added D-lactate also increased oxygen consumption rates of proliferating T cells, compared to NaCl controls, by 56.1 ±35.1% (p<0.05, n=4). In contrast, methyl-esters of L- and D-lactate resistant to either lactate dehydrogenase isoform did not reduce T cell homeostatic proliferation. Our data show that D-lactate has in vivo immunosuppressive effects and can induce de-novo iTregs. The process of lactate oxidation is likely required for its immune modulatory effects.

CITATION INFORMATION: Beier U, Jiao J, Xiao H, Angelin A, Wallace D, Levine M, Hancock W. Learning from Cancer: Using D-Lactate for Therapeutic Immunosuppression. Am J Transplant. 2016;16 (suppl 3).

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