JCI Insight (Oct 2023)

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

  • Fumimasa Kitamura,
  • Takashi Semba,
  • Noriko Yasuda-Yoshihara,
  • Kosuke Yamada,
  • Akiho Nishimura,
  • Juntaro Yamasaki,
  • Osamu Nagano,
  • Tadahito Yasuda,
  • Atsuko Yonemura,
  • Yilin Tong,
  • Huaitao Wang,
  • Takahiko Akiyama,
  • Kazuki Matsumura,
  • Norio Uemura,
  • Rumi Itoyama,
  • Luke Bu,
  • Lingfeng Fu,
  • Xichen Hu,
  • Feng Wei,
  • Kosuke Mima,
  • Katsunori Imai,
  • Hiromitsu Hayashi,
  • Yo-ichi Yamashita,
  • Yuji Miyamoto,
  • Hideo Baba,
  • Takatsugu Ishimoto

Journal volume & issue
Vol. 8, no. 20

Abstract

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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.

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