Cancer-associated fibroblasts reuse cancer-derived lactate to maintain a fibrotic and immunosuppressive microenvironment in pancreatic cancer
Fumimasa Kitamura, … , Hideo Baba, Takatsugu Ishimoto
Fumimasa Kitamura, … , Hideo Baba, Takatsugu Ishimoto
Published September 21, 2023
Citation Information: JCI Insight. 2023;8(20):e163022. https://doi.org/10.1172/jci.insight.163022.
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Research Article Metabolism Oncology

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

Abstract

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.

Authors

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

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Figure 5

Lactate-stimulated CAFs produce IL-6 and suppress antitumor immunity.

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Lactate-stimulated CAFs produce IL-6 and suppress antitumor immunity. (A...
(A) CIBERSORT analysis of estimated CD8+ T cell infiltration in tumors in the LDHA-high and LDHA-low subgroups of PDAC patients from the TCGA cohort (n = 177). (B) Heatmap of the mRNA expression of immunosuppression-related genes in CAFs stimulated with or without lactate (n = 3). (C) Volcano plot of the mRNA expression of CAFs stimulated with or without lactate (n = 3). (D) Quantification of IL6 and PIGF expression in CAFs stimulated with or without lactate by quantitative PCR (n = 3). (E) Quantification of the IL-6 concentration in the conditioned medium of CAFs stimulated with or without lactate (n = 6). Box plots show the interquartile range (box), median (line), and minimum and maximum (whiskers). (F) Schematic of the experimental model for analysis of the cytotoxic activity of CD8+ T cells. PBMCs were isolated from healthy donors and stimulated with PBS, lactate, IL-6, or lactate plus IL-6. After 48 hours, the cells were analyzed by flow cytometry. (G) Quantification of GraB (top) and IFN-γ (bottom) expression in CD8+ T cells stimulated as described in F by flow cytometry (n = 3). *P < 0.05. A Student’s t test was used to compare continuous variables between 2 groups. One-way ANOVA followed by Tukey’s multiple-comparison test was used to compare multiple groups.