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Targeting MEK/COX-2 axis improve immunotherapy efficacy in dMMR colorectal cancer with PIK3CA overexpression

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Abstract

Purpose

PIK3CA mutation or overexpression is associated with immunotherapy resistance in multiple cancer types, but is also paradoxically associated with benefit of COX-2 inhibition on patient survival of colorectal cancer (CRC) with mismatch repair deficiency (dMMR). This study examined whether and how PIK3CA status affected COX-2-mediated tumor inflammation and immunotherapy response of dMMR CRC.

Methods

Murine colon cancer cells MC38, CT26, and CT26-Mlh1-KO were used to construct PIK3CA knockdown and overexpression models to mimic dMMR CRC with PIK3CA dysregulation, and xenograft models were used to evaluate how PIK3CA regulate COX-2 expression, CD8+ T cells infiltration, tumor growth, and therapy response to anti-PD-L1 treatment using immunocompetent mice. Western blot was carried out to delineate the signaling pathways in human and mouse cancer cells, and immunohistochemical analysis together with bioinformatics analysis using human patient samples.

Results

PIK3CA upregulates COX-2 expression through MEK/ERK signaling pathway independent of AKT signaling to promote tumor inflammation and immunosuppression. PIK3CA knockdown profoundly reduced CT26 tumor growth in a CD8+ T cell-dependent manner, while PIK3CA overexpression significantly inhibited CD8+ T cells infiltration and promoted tumor growth. Furthermore, MEK or COX-2 inhibition augmented the anti-tumor activity of anti-PD-L1 immunotherapy on dMMR CRC mouse models, accompanied with increased CD8+ T cells infiltration and activated tumor microenvironment.

Conclusion

Our results identified that the PIK3CA hyperactivation in dMMR CRC upregulated COX-2 through MEK signaling, which inhibited CD8+ T cells infiltration and promoted tumor growth, together led to immunotherapy resistance. COX-2 or MEK inhibition may relieve therapy resistance and promote therapy efficacy of anti-PD-1/PD-L1 immunotherapy for treating dMMR CRC with PIK3CA overexpression or activating mutation.

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Data availability

The data are available from the corresponding authors upon reasonable request.

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Acknowledgements

We thank Dr. Wenjing Xiong of Sun Yat-sen University Cancer Center for technical assistance. This work was supported by grants from the National Natural Science Foundation of China (82102995, 81972692, 82073140, 81902905, 81902491), Tencent Foundation (SYSU-84000-20220420-0001), and Guangdong Basic and Applied Basic Research Foundation (2021A1515012080).

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Author notes

  1. Kunwei Peng, Yongxiang Liu and Shousheng Liu are contributed equally to this work.

Authors and Affiliations

  1. State Key Laboratory of Oncology in South China, Guangdong Provincial Clinical Research Center for Cancer, Sun Yat-sen University Cancer Center, 651 Dongfeng East Road, Guangzhou, Guangdong, 510060, China

    Kunwei Peng, Yongxiang Liu, Shousheng Liu, Zining Wang, Huanling Zhang, Wenzhuo He, Yanan Jin, Lei Wang, Xiaojun Xia & Liangping Xia

  2. VIP Region, Sun Yat-sen University Cancer Center, Guangzhou, Guangdong, China

    Kunwei Peng, Shousheng Liu, Wenzhuo He, Yanan Jin, Lei Wang & Liangping Xia

  3. Department of Medical Oncology, The Second Affiliated Hospital of Guangzhou Medical University, No. 250 Changgang East Road, Guangzhou, China

    Kunwei Peng

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  2. Yongxiang Liu
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Contributions

K.P., X.X. and L.X. conceived and designed the study. K.P. conducted most experiments and wrote the manuscript. Y.L. and S.L. performed some key experiments; Z.W., H.Z., W.H., Y.J. and L.W. performed parts of the experiments. X.X. and L.X. supervised the project and revised the manuscript. All authors read and approved the final manuscript.

Corresponding authors

Correspondence to Xiaojun Xia or Liangping Xia.

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Ethical approval

The study was approved by the Ethics Committee of Sun Yat-Sen University Cancer Center, and all patients had been provided written informed consent for their data and surgical specimens to be used for research purposes. All mice were maintained under Specific Pathogen-Free (SPF) conditions and in accordance with the animal experiment guidelines of Sun Yat-sen University (Guangzhou, China). All animal procedures were approved by the Institutional Animal Care and Use Committee of Sun Yat-sen University (Guangzhou, China).

Competing interests

None declared.

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Peng, K., Liu, Y., Liu, S. et al. Targeting MEK/COX-2 axis improve immunotherapy efficacy in dMMR colorectal cancer with PIK3CA overexpression. Cell Oncol. (2024). https://doi.org/10.1007/s13402-024-00916-y

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