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

• Published in: Cancer research (Chicago, Ill.) Ill.), 2017-07, Vol.77 (13), p.3632-3643
• Main Authors: Seth, Pankaj, Csizmadia, Eva, Hedblom, Andreas, Vuerich, Marta, Xie, Han, Li, Mailin, Longhi, Maria Serena, Wegiel, Barbara
• Format: Article
• Language: English
• Subjects: Angiogenesis; Animal models; Animals; Cancer; CD3 antigen; CD8 antigen; CD86 antigen; Cell activation; Cell Line, Tumor; Clonal deletion; Cytotoxicity, Immunologic; Dehydrogenase; Dehydrogenases; Humans; Immune response; Immunosuppression; Interleukin 1; Interleukin 17; Isoenzymes - deficiency; Isoenzymes - immunology; Isoenzymes - metabolism; K-Ras protein; L-Lactate dehydrogenase; L-Lactate Dehydrogenase - deficiency; L-Lactate Dehydrogenase - immunology; L-Lactate Dehydrogenase - metabolism; Lactic acid; Lung carcinoma; Lung Neoplasms - enzymology; Lung Neoplasms - immunology; Lymphocytes; Lymphocytes T; Macrophages; Mice; Mice, Inbred C57BL; Myeloid cells; Myeloid Cells - enzymology; Myeloid Cells - immunology; Myeloid Cells - pathology; PD-L1 protein; Tumor Microenvironment - immunology; Tumors; Vascular endothelial growth factor; γ-Interferon
• ISSN: 0008-5472; 1538-7445
• DOI: 10.1158/0008-5472.can-16-2938

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 and MCP-1 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. .