Learning from Cancer: Using D-Lactate for Therapeutic Immunosuppression.
1Pediatric Nephrology, Children's Hospital of Philadelphia and University of Pennsylvania, Philadelphia, PA
2Center for Mitochondrial and Epigenomic Medicine, Children's Hospital of Philadelphia, Philadelphia, PA
3Department of Surgery, University of Pennsylvania, Philadelphia, PA
4Department of Pathology and Laboratory Medicine, Children's Hospital of Philadelphia and Univerisity of Pennsylvania, Philadelphia, PA.
Meeting: 2016 American Transplant Congress
Abstract number: A26
Keywords: Immunosuppression, T cells
Session Information
Session Type: Poster Session
Date: Saturday, June 11, 2016
Session Time: 5:30pm-7:30pm
Presentation Time: 5:30pm-7:30pm
Location: Halls C&D
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).
To cite this abstract in AMA style:
Beier U, Jiao J, Xiao H, Angelin A, Wallace D, Levine M, Hancock W. Learning from Cancer: Using D-Lactate for Therapeutic Immunosuppression. [abstract]. Am J Transplant. 2016; 16 (suppl 3). https://atcmeetingabstracts.com/abstract/learning-from-cancer-using-d-lactate-for-therapeutic-immunosuppression/. Accessed December 4, 2024.« Back to 2016 American Transplant Congress