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Translational Therapeutics

Death receptors 4/5 mediate tumour sensitivitNot applicably to natural killer cell-mediated cytotoxicity in mismatch repair deficient colorectal cancer

Background

Identifying the target of natural killer (NK) cells in colorectal cancer (CRC) is critical for optimising the clinical use of NK cell-mediated immunotherapy. Mismatch repair deficiency (dMMR) is associated with high immune cell infiltration and MHC Class I defects. Whether dMMR CRC responses to NK cell therapy remains unclear.

Methods

MLH1, DR4, and DR5 knockout cell lines were established using CRISPR-Cas9 system. NK92-MI or NK cell isolated from BABL/C mice were used as effector cells against tumour cells. Inflammatory cytokines secretion by CRC cells was assessed via cytokine analysis. NK-cell-deficient/proficient animal models were used to validate the NK cell sensitivity.

Results

We observed that dMMR CRC cells were more sensitive to NK cell-mediated cytotoxicity than were mismatch-repair-proficient (pMMR) CRC cells. In dMMR CRC, Death receptor (DR)4/5 was upregulated and mediated sensitivity to NK cell-mediated cytotoxicity. DR4/5-mediated secretion of interleukin -12 sustained NK cell viability in dMMR CRC. NK cell depletion induced dMMR CRC tumour growth, and NK cell transfer inhibited lung metastasis of dMMR CRC with DR4/5 expression in vivo. TP53 upregulated DR4/DR5 expression in dMMR CRC.

Conclusions

dMMR associated with increased sensitivity to NK cell-mediated cytotoxicity in CRC. DR4/DR5 sensitise dMMR CRC to NK cell-mediated cytotoxicity.

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Fig. 1: dMMR status associated with increased sensitivity to NK cell-mediated cytotoxicity in CRC cells.
Fig. 2: DR4/5 are significantly up-regulated in dMMR CRC.
Fig. 3: DR4/DR5 sensitise dMMR CRC cells to NK cell-mediated cytotoxicity.
Fig. 4: DR4/5 induced IL-12 secretion via NF-κb2 signalling in dMMR CRC.
Fig. 5: DR4/5 are required for NK cell-mediated anti-tumour effect on dMMR CRC.
Fig. 6: TP53 upregulates DR4/5 expression in dMMR CRC.

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Data availability

The datasets supporting the conclusions of this article were deposited in the Research Data Deposit system of Sun Yat-sen University Cancer (RDDB2024581025) and can be obtained from the corresponding authors on reasonable request.

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Acknowledgements

We would like to thank the professor Xiaojun Xia (State Key Laboratory of Oncology in South China, Collaborative Innovation Center of Cancer Medicine, Sun Yat-sen University Cancer Center, Guangzhou, China) for the enormous contribution to our manuscript.

Funding

This study was supported by the National Natural Science Foundation of China (No. 82002557 to LY; No. 82202850 to ZCX) and the Basic and applied research of science and technology in Guangzhou (2023A04J2392).

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LY, conceived and designed the experiments; JHY, ZCX designed the experiments; ZCX wrote the manuscript; LY, PFK, and QKX performed the experiments; QKX, WZH and YNJ analyzed the data; PFK and QKX helped in interpretation of the results; ZCX and LPX revised the manuscript based on the comments of reviewers. All authors approved the final version.

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Correspondence to Zhenchong Xiong or Liangping Xia.

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Yang, L., Yi, J., He, W. et al. Death receptors 4/5 mediate tumour sensitivitNot applicably to natural killer cell-mediated cytotoxicity in mismatch repair deficient colorectal cancer. Br J Cancer (2024). https://doi.org/10.1038/s41416-024-02673-z

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