Mutant p53 achieved Gain-of-Function by promoting tumor growth and immune escape through PHLPP2/AKT/PD-L1 pathway

Liu, Nannan; Jiang, Xinxiu; Guo, Leiming; Zhang, Chuchu; Jiang, Meimei; Sun, Zhuoran; Zhang, Yizheng; Mi, Wunan; Li, Jiehan; Fu, Yang; Wang, Feng; Zhang, Lingling; Zhang, Yingjie

doi:10.7150/ijbs.67200

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Theranostics

International Journal of Medical Sciences

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Int J Biol Sci 2022; 18(6):2419-2438. doi:10.7150/ijbs.67200 This issue Cite

Research Paper

Mutant p53 achieved Gain-of-Function by promoting tumor growth and immune escape through PHLPP2/AKT/PD-L1 pathway

Nannan Liu¹, Xinxiu Jiang^1,2, Leiming Guo^3,4, Chuchu Zhang¹, Meimei Jiang¹, Zhuoran Sun², Yizheng Zhang^1,5, Wunan Mi^1,5, Jiehan Li^1,5, Yang Fu⁵, Feng Wang^3✉, Lingling Zhang^2✉, Yingjie Zhang^1,6✉

1. School of Biomedical Sciences, Hunan University, Changsha, China.
2. Department of Laboratory Medicine, the Third Xiangya Hospital, Central South University, Changsha, China.
3. Department of Gastroenterology, Huadong Hospital, Shanghai Medical College, Fudan University, Shanghai, China.
4. Department of R&D, Shanghai Creative Immune Therapeutics Co., Ltd, Shanghai, China.
5. Department of Gastroenterology, the First Affiliated Hospital of Zhengzhou University, Zhengzhou, 450052, China.
6. College of Biology, Hunan University, Changsha, China.

Citation:

Liu N, Jiang X, Guo L, Zhang C, Jiang M, Sun Z, Zhang Y, Mi W, Li J, Fu Y, Wang F, Zhang L, Zhang Y. Mutant p53 achieved Gain-of-Function by promoting tumor growth and immune escape through PHLPP2/AKT/PD-L1 pathway. Int J Biol Sci 2022; 18(6):2419-2438. doi:10.7150/ijbs.67200. https://www.ijbs.com/v18p2419.htm

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Abstract

The most frequent genetic alterations of the TP53 gene in human cancer were reported. TP53 mutation gains new function as a target of genetic instability, which is associated with increased tumor progression and poor survival rate in patients. In this study, more than three hundred colorectal cancer patients' samples were firstly analyzed, and the results showed that patients with mutant p53 had higher levels of AKT phosphorylation and PD-L1 expression, which were next verified both in cell lines in vitro and patients' samples in vivo. Further studies demonstrated that the hotspot of mutant p53 directly binds to the promoter of PHLPP2 to inhibit its transcription, and resulting in down-regulating its protein expressional level. Subsequently, AKT was released and activated, promoting tumor proliferation and metastasis. In parallel, 4EBP1/eIF4E was identified as downstream executors of AKT to enhance the translational level of PD-L1, which decreased the activation of T cells. Besides, inhibiting AKT/mTOR pathway significantly suppressed PD-L1 expression, tumor growth, and immune escape in p53 mutated cells. In conclusion, mutant p53 achieved its Gain-of-Function by transcriptionally inhibiting PHLPP2 and activating AKT, which suppresses immune response and advances tumor growth. Thus, this study provides an excellent basis for a further understanding of the clinical treatment of neoplastic diseases for patients with mutant p53, with an emphasis on immunotherapy.

Keywords: mutant TP53, PHLPP2, AKT, PD-L1, immunity

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APA

Liu, N., Jiang, X., Guo, L., Zhang, C., Jiang, M., Sun, Z., Zhang, Y., Mi, W., Li, J., Fu, Y., Wang, F., Zhang, L., Zhang, Y. (2022). Mutant p53 achieved Gain-of-Function by promoting tumor growth and immune escape through PHLPP2/AKT/PD-L1 pathway. International Journal of Biological Sciences, 18(6), 2419-2438. https://doi.org/10.7150/ijbs.67200.

ACS

Liu, N.; Jiang, X.; Guo, L.; Zhang, C.; Jiang, M.; Sun, Z.; Zhang, Y.; Mi, W.; Li, J.; Fu, Y.; Wang, F.; Zhang, L.; Zhang, Y. Mutant p53 achieved Gain-of-Function by promoting tumor growth and immune escape through PHLPP2/AKT/PD-L1 pathway. Int. J. Biol. Sci. 2022, 18 (6), 2419-2438. DOI: 10.7150/ijbs.67200.

NLM

CSE

Liu N, Jiang X, Guo L, Zhang C, Jiang M, Sun Z, Zhang Y, Mi W, Li J, Fu Y, Wang F, Zhang L, Zhang Y. 2022. Mutant p53 achieved Gain-of-Function by promoting tumor growth and immune escape through PHLPP2/AKT/PD-L1 pathway. Int J Biol Sci. 18(6):2419-2438.

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