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Demethylase JMJD2D induces PD-L1 expression to promote colorectal cancer immune escape by enhancing IFNGR1-STAT3-IRF1 signaling

Oncogene volume 41, pages 1421–1433 (2022)Cite this article

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Abstract

Programmed death-ligand 1 (PD-L1) is an important immunosuppressive molecule highly expressed on the surface of cancer cells. IFNγ triggered cancer cell immunosuppression against CD8+ T cell surveillance via up-regulation of PD-L1. Histone demethylase JMJD2D promotes colorectal cancer (CRC) progression; however, the role of JMJD2D in cancer immune escape is unknown. Here, we report that both PD-L1 and JMJD2D are frequently overexpressed in human CRC specimens with a significant positive correlation. Genetic ablation of JMJD2D in CRC cells attenuated the expression of PD-L1 and stalled tumor growth in mice, accompanied by the elevated number and effector function of tumor infiltrating CD8+ T cells. Mechanistically, JMJD2D coactivated SP-1 to promote the expression of IFNGR1, which elevated STAT3-IRF1 signaling and promoted PD-L1 expression. Again, JMJD2D is a major coactivator for STAT3-IRF1 axis to enhance PD-L1 transcription in a demethylation activity dependent manner. Furthermore, pharmacological inhibition of JMJD2D conduced to improve the anti-tumor efficacy of PD-L1 antibody as demonstrated by slower tumor growth and higher infiltration and function of CD8+ T cells in the combination of JMJD2D inhibitor 5-c-8HQ and PD-L1 antibody group compared with monotherapy with either agent. These results demonstrate that JMJD2D promotes CRC immune escape by enhancing PD-L1 expression to inhibit the activation and tumor infiltration of CD8+ T cells; targeting JMJD2D has the potential role in promoting the efficacy of anti-PD-1/PD-L1 immunotherapy.

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Fig. 1: JMJD2D promotes CRC immune escape via modulating PD-L1 expression.
Fig. 2: JMJD2D promotes CRC cell immunosuppression against T cell activation and infiltration via upregulating PD-L1.
Fig. 3: JMJD2D mediates PD-L1 expression by regulating IFNGR1.
Fig. 4: JMJD2D coactivates SP-1 to enhance IFNGR1 transcription.
Fig. 5: JMJD2D is required for IFNγ-mediated PD-L1 overexpression via regulating IFNGR1-STAT3-IRF1 signaling.
Fig. 6: JMJD2D cooperates with STAT3-IRF1 axis to promote PD-L1 expression.
Fig. 7: JMJD2D inhibitor 5-c-8HQ improves the anti-tumor efficacy of PD-L1 antibody.

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Data availability

The datasets used and/or analyzed during the current study are available from the corresponding author on reasonable request.

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Acknowledgements

This work was supported by the National Natural Science Foundation of China (No. 81970485 and No. 81772942 to Chundong Yu, No. 31570883 to Nengming Xiao, No. 81972223 to Wengang Li); Scientific Research Foundation for Advanced Talents, Xiang’an Hospital of Xiamen University (No. PM20180917008 to Wengang Li).

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Authors and Affiliations

  1. State Key Laboratory of Cellular Stress Biology, Innovation Center for Cell Biology, School of Life Sciences, Xiamen University, Xiamen, China

    Qiang Chen, Shuqing Zhuang, Yilin Hong, Lingtao Yang, Peng Guo, Pingli Mo, Nengming Xiao & Chundong Yu

  2. Department of Cellular and Genetic Medicine, School of Basic Medical Sciences, Fudan University, Shanghai, China

    Kesong Peng

  3. Cancer Research Center, School of Medicine, Xiamen University, Xiamen, China

    Wengang Li

  4. Xiamen University Research Center of Retroperitoneal Tumor Committee of Oncology Society of Chinese Medical Association, Xiang’an Hospital of Xiamen University, School of Medicine, Xiamen University, Xiamen, China

    Wengang Li

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  1. Qiang Chen
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Contributions

Study concept and design: QC, KP, WL, NX, and CY; Experimental studies: QC, KP, SZ, YH, LY, PG, and PM; Statistical analysis: QC, KP, Obtained funding: WL, NX, and CY; Drafting of the paper: QC, KP, and CY.

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Correspondence to Kesong Peng, Wengang Li, Nengming Xiao or Chundong Yu.

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All animal experiments were conducted under protocols approved by the Laboratory Animal Center of Xiamen University. For experiments using human specimens, all specimens were anonymously coded in accordance with the Declaration of Helsinki. The study protocol that conformed to the ethical guidelines was approved by the Medical Ethics Committee at school of medicine, Xiamen University.

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Chen, Q., Zhuang, S., Hong, Y. et al. Demethylase JMJD2D induces PD-L1 expression to promote colorectal cancer immune escape by enhancing IFNGR1-STAT3-IRF1 signaling. Oncogene 41, 1421–1433 (2022). https://doi.org/10.1038/s41388-021-02173-x

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