Activated HIF1α of tumor cells promotes chemoresistance development via recruiting GDF15-producing tumor-associated macrophages in gastric cancer

• Published in: Cancer Immunology, Immunotherapy Immunotherapy, 2020-10, Vol.69 (10), p.1973-1987
• Main Authors: Yu, Shan, Li, Qian, Yu, Yiyi, Cui, Yuehong, Li, Wei, Liu, Tianshu, Liu, Fenglin
• Format: Article
• Language: English
• Subjects: Animals; Apoptosis; Biomarkers, Tumor - genetics; Biomarkers, Tumor - metabolism; Cancer Research; Cell Proliferation; Drug Resistance, Neoplasm; Female; Gene Expression Regulation, Neoplastic; Growth Differentiation Factor 15 - genetics; Growth Differentiation Factor 15 - metabolism; Humans; Hypoxia-Inducible Factor 1, alpha Subunit - genetics; Hypoxia-Inducible Factor 1, alpha Subunit - metabolism; Immunology; Macrophages - drug effects; Macrophages - immunology; Macrophages - metabolism; Macrophages - pathology; Medicine; Medicine & Public Health; Mice; Mice, Inbred BALB C; Mice, Inbred C57BL; Mice, Nude; Oncology; Original; Original Article; Signal Transduction; Stomach Neoplasms - drug therapy; Stomach Neoplasms - immunology; Stomach Neoplasms - metabolism; Stomach Neoplasms - pathology; Tumor Cells, Cultured; Tumor Microenvironment - drug effects; Tumor Microenvironment - immunology; Xenograft Model Antitumor Assays
• ISSN: 0340-7004; 1432-0851
• DOI: 10.1007/s00262-020-02598-5

Chemotherapy is the preferred treatment for advanced stage gastric cancer (GC) patients, and developing chemoresistance is a tremendous challenge to efficacy of GC treatment. The treatments of anti-tumor chemo-agents recruit more tumor-associated macrophages (TAMs) which are highly implicated in the chemoresistance development, but the underlying molecular mechanism is unclear. Here, we demonstrate that hypoxia-inducible factor 1α (HIF1α) in GC cells is activated upon 5-fluorouracil (5-FU) treatment and results in much more accumulation of M2-type TAMs which protect tumor cells from chemo-agents. Mechanistically, in the GC cells under the 5-FU treatment, reactive oxygen species is accumulated and then induces the activation of HIF1α signaling to drive the expression of high-mobility group box 1, which leads to more macrophage’s infiltration into GC tumor. In turn, the recruited TAMs exhibit tumor-protected M2-type phenotype and promote the chemoresistance of GC cells via producing growth differentiation factor 15 (GDF15) to exacerbate the fatty acid β-oxidation in tumor cells. Blocking GDF15 using antibody or inhibiting FAO of tumor cells by etomoxir efficiently gave rise to the tumor cell sensitivity to 5-FU. Therefore, our study demonstrates a novel insight in understanding the cross talking between tumor cells and immune microenvironment and provides new therapeutic targets for clinic treatments of gastric cancer.