Deletion of Lactate Dehydrogenase-A in Myeloid Cells Triggers Antitumor Immunity

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 CD86(high) and MCP-1(high) 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 IFN gamma-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.