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OLFM4 deficiency delays the progression of colitis to colorectal cancer by abrogating PMN-MDSCs recruitment

Oncogene volume 41, pages 3131–3150 (2022)Cite this article

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Abstract

Chronic inflammatory bowel disease (IBD) is strongly associated with the development of colitis-associated tumorigenesis (CAT). Despite recent advances in the understanding of polymorphonuclear myeloid-derived suppressor cell (PMN-MDSC) responses in cancer, the mechanisms of these cells during this process remain largely uncharacterized. Here, we discovered a glycoprotein, olfactomedin-4 (OLFM4), was highly expressed in PMN-MDSCs from colitis to colorectal cancer (CRC), and its expression level and PMN-MDSC population positively correlated with the progression of IBD to CRC. Moreover, mice lacking OLFM4 in myeloid cells showed poor recruitment of PMN-MDSCs, impaired intestinal homeostasis, and delayed development from IBD to CRC, and increased response to anti-PD1 therapy. The main mechanism of OLFM4-mediated PMN-MDSC activity involved the NF-κB/PTGS2 pathway, through the binding of LGALS3, a galactoside-binding protein expressed on PMN-MDSCs. Our results showed that the OLFM4/NF-κB/PTGS2 pathway promoted PMN-MDSC recruitment, which played an essential role in the maintenance of intestinal homeostasis, but showed resistance to anti-PD1 therapy in CRC.

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Fig. 1: High expression level of OLFM4 is accompanied by polymorphonuclear myeloid-derived suppressor cells (PMN-MDSCs) recruitment during colitis-associated tumorigenesis (CAT) in humans.
Fig. 2: High expression level of OLFM4 is accompanied by PMN-MDSCs recruitment during colitis-associated tumorigenesis (CAT) in mice.
Fig. 3: OLFM4 deficiency in myeloid cells abrogates the recruitment of polymorphonuclear myeloid-derived suppressor cells (PMN-MDSCs), impairs intestinal homeostasis, and delays the progression of colonic inflammation to CRC.
Fig. 4: OLFM4 deletion influences the role of polymorphonuclear myeloid-derived suppressor cells (PMN-MDSCs) in the alleviation of acute colitis.
Fig. 5: OLFM4 deficiency in myeloid cells increases response to anti-PD-1 therapy in mice.
Fig. 6: OLFM4 activates polymorphonuclear myeloid-derived suppressor cells (PMN-MDSCs) through the NF-κB/PTGS2 signaling pathway.
Fig. 7: LGALS3 interacts with OLFM4 on polymorphonuclear myeloid-derived suppressor cells (PMN-MDSCs).
Fig. 8: Interrupting OLFM4/LGALS3 interaction decline NF-κB/PTGS2 signaling.

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Acknowledgements

We thank XL and YZ from Southern Medical University for their technical assistance. We thank ZXL from South China University of Technology, ZPZ and LZ from Southern Medical University for their mice resource support. We thank XD. Wu from Tianjin Medical University for providing murine myeloid cell line 32D. We also thank YXZ and LD from Yangzhou University for providing the BiFC vector. Flow cytometry used in this work was supported by the Department of Immunology at the School of Basic Medical Sciences, the Southern Medical University, and Department of Developmental Biology at the School of Basic Medical Sciences, the Southern Medical University. This work was supported by the following grants to YMH: the High level Talent Start-up Funding of Southern Medical University, the National Natural Science Foundation of China (grants 82171706, 81971420, and 81991511), the Guangdong Special Support Program for Youth Science and Technology Innovation Talents (grant 2019TQ05Y585), the National Natural Science Foundation of Guangdong (grant 2019A1515011435), the College Students’ Innovative Entrepreneurial Training Plan Program (grant S202012121102), and the post-doctoral research project start-up funding of Affiliated Dongguan Hospital (grant 294526 to ZYC). It was also supported by the Dongguan Science and Technology of Social Development Program (grant 2019507163147 to LXH).

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  1. These authors contributed equally: Ziyang Chen, Xiaogang Zhang, Zhe Xing.

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  1. Department of Neurosurgery, Affiliated Dongguan Hospital, Southern Medical University (Dongguan People’s Hospital), Dongguan, China

    Ziyang Chen & Yumei He

  2. Department of Immunology, School of Basic Medical Sciences, Southern Medical University, Guangzhou, China

    Ziyang Chen, Xiaogang Zhang, Zhe Xing, Shuaijun Lv, Xinyao Li, Meiqi Chen, Shaowen Zuo, Yingxu Tao & Yumei He

  3. Dongguan Institute of Clinical Cancer Research, Department of Medical Oncology, Affiliated Dongguan Hospital, Southern Medical University (Dongguan People’s Hospital), Dongguan, China

    Linxuan Huang

  4. Department of Clinical Laboratory, the Third Affiliated Hospital of Southern Medical University, Southern Medical University, Guangzhou, China

    Jingping Liu & Yumei He

  5. Department of Gastroenterology, the Sixth Affiliated Hospital, Sun Yat-sen University, Guangzhou, China

    Shubiao Ye

  6. Guangdong Provincial Key Laboratory of Single Cell Technology and Application, Southern Medical University, Guangzhou, China

    Yumei He

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YMH: designed and supervised the study, and wrote the manuscript; ZYC, XGZ, and ZX: performed most experiments and analyzed the data. SJLv, LXH, JPL, SBY, XYL, MQC, SWZ, and YXT participated in the experiments. All the authors have read the manuscript and provided useful comments.

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Chen, Z., Zhang, X., Xing, Z. et al. OLFM4 deficiency delays the progression of colitis to colorectal cancer by abrogating PMN-MDSCs recruitment. Oncogene 41, 3131–3150 (2022). https://doi.org/10.1038/s41388-022-02324-8

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