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 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. Further, it was associated with more pronounced antitumor T cell immunity via induction of IL-17 and IFNγ-producing CD8+ T (Tc17 and Tc1) cells, likely via suppression of lactate-driven PD-L1 expression. Our results suggest that expression 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.

from #AlexandrosSfakianakis via Alexandros G.Sfakianakis on Inoreader http://ift.tt/2oNWyJV
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