Deletion of Lactate Dehydrogenase-A in Myeloid Cells Triggers Antitumor Immunity
Abstract
Immunometabolism is emerging as a critical determinant of cancer pathophysiology. In this study, we explored the contributions of macrophage-expressed lactate dehydrogenase-A (LDH-A) to tumor formation in a K-Ras murine model of lung carcinoma. Myeloid-specific deletion of LDH-A promoted accumulation of macrophages with a CD86high and MCP-1high M1-like phenotype that suppressed tumor growth. This phenotypic effect was accompanied by reduced VEGF expression and angiogenesis, diminished numbers of PD-L1+ cancer cells, increased numbers of CD3+ T cells, and activation status of CD8+ T cells. Furthermore, it was associated with more pronounced antitumor T-cell immunity via induction of IL17 and IFNγ-producing CD8+ T (Tc17 and Tc1) cells, likely via suppression of lactate-driven PD-L1 expression. Our results suggest that expressions of LDH-A and lactate by macrophage in the tumor microenvironment are major drivers of T-cell immunosuppression, strongly supporting the concept of targeting stromal LDH-A as an effective strategy to blunt tumoral immune escape. Cancer Res; 77(13); 3632–43. ©2017 AACR.
Document Details
- Document Type
- Pub Defense Publication
- Publication Date
- Jul 01, 2017
- Source ID
- 10.1158/0008-5472.can-16-2938
Entities
People
- Andreas Hedblom
- Barbara Wegiel
- Eva Csizmadia
- Han Xie
- Mailin Li
- Maria Serena Longhi
- Marta Vuerich
- Pankaj Seth
Organizations
- American Heart Association
- Beth Israel Deaconess Medical Center
- Congressionally Directed Medical Research Programs