Cancer-associated fibroblasts reuse cancer-derived lactate to maintain a fibrotic and immunosuppressive microenvironment in pancreatic cancer

Glycolysis is highly enhanced in pancreatic ductal adenocarcinoma (PDAC) cells; thus, glucose restrictions are imposed on nontumor cells in the PDAC tumor microenvironment (TME). However, little is known about how such glucose competition alters metabolism and confers phenotypic changes in stromal cells in the TME. Here, we report that cancer-associated fibroblasts (CAFs) with restricted glucose availability utilize lactate from glycolysis-enhanced cancer cells as a fuel and exert immunosuppressive activity in the PDAC TME. The expression of lactate dehydrogenase A (LDHA), which regulates lactate production, was a poor prognostic factor for patients with PDAC, and LDHA depletion suppressed tumor growth in a CAF-rich murine PDAC model. Coculture of CAFs with PDAC cells revealed that most of the glucose was taken up by the tumor cells and that CAFs consumed lactate via monocarboxylate transporter 1 to enhance proliferation through the TCA cycle. Moreover, lactate-stimulated CAFs upregulated IL-6 expression and suppressed cytotoxic immune cell activity synergistically with lactate. Finally, the LDHA inhibitor FX11 reduced tumor growth and improved antitumor immunity in CAF-rich PDAC tumors. Our study provides insight regarding the crosstalk among tumor cells, CAFs, and immune cells mediated by lactate and offers therapeutic strategies for targeting LDHA enzymatic activity in PDAC cells.

Automated summary

Glycolysis is increased in pancreatic ductal adenocarcinoma (PDAC) cells, resulting in glucose restrictions on nontumor cells in the tumor microenvironment. Cancer-associated fibroblasts (CAFs) with restricted glucose availability utilize lactate as a fuel and exhibit immunosuppressive activity in the PDAC microenvironment. Coculture experiments revealed that glucose is mainly consumed by tumor cells, while CAFs consume lactate through monocarboxylate transporter 1 to enhance proliferation. Lactate-stimulated CAFs upregulate IL-6 expression and synergistically suppress cytotoxic immune cell activity with lactate. Inhibiting lactate dehydrogenase A (LDHA) reduces tumor growth and improves antitumor immunity in CAF-rich PDAC tumors.