TY - JOUR
T1 - Cancer-associated fibroblasts reuse cancer-derived lactate to maintain a fibrotic and immunosuppressive microenvironment in pancreatic cancer
AU - Kitamura, Fumimasa
AU - Semba, Takashi
AU - Yasuda-Yoshihara, Noriko
AU - Yamada, Kosuke
AU - Nishimura, Akiho
AU - Yamasaki, Juntaro
AU - Nagano, Osamu
AU - Yasuda, Tadahito
AU - Yonemura, Atsuko
AU - Tong, Yilin
AU - Wang, Huaitao
AU - Akiyama, Takahiko
AU - Matsumura, Kazuki
AU - Uemura, Norio
AU - Itoyama, Rumi
AU - Bu, Luke
AU - Fu, Lingfeng
AU - Hu, Xichen
AU - Wei, Feng
AU - Mima, Kosuke
AU - Imai, Katsunori
AU - Hayashi, Hiromitsu
AU - Yamashita, Yo Ichi
AU - Miyamoto, Yuji
AU - Baba, Hideo
AU - Ishimoto, Takatsugu
N1 - Publisher Copyright:
© 2023, Kitamura et al.
PY - 2023/10
Y1 - 2023/10
N2 - 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.
AB - 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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U2 - 10.1172/jci.insight.163022
DO - 10.1172/jci.insight.163022
M3 - Article
C2 - 37733442
AN - SCOPUS:85175026715
SN - 2379-3708
VL - 8
JO - JCI insight
JF - JCI insight
IS - 20
M1 - e163022
ER -