Nat Immunol | Zou Weiping's group reveals the mechanism of MDM2-STAT5 signaling pathway regulating T cell-mediated tumor immunity

Editor-in-Chief | The occurrence and development of tumors is a very complex process involving many genes and signal pathways.

In about 50% of human tumors, p53 protein will be due to gene mutations, deletions or abnormal degradation, resulting in the loss of p53 inhibition of tumor function.

In some tumor cells, the ubiquitin E3 ligase MDM2 is overexpressed, which binds to the p53 protein and promotes its ubiquitination degradation, directly reducing the stability and activity of the p53 protein, and helping tumors escape the blow [1].

Based on this, the design and development of anti-tumor drugs with a new mechanism based on MDM2-p53 is one of the hot spots and priorities in the current global tumor drug research and development field [2].

In addition, MDM2 also has oncogenic activity independent of p53, and drugs targeting MDM2 are also under research and development [3].

At present, no therapeutic drugs targeting MDM2 have been approved, and the related signaling pathways of MDM2 are still poorly understood in tumor immunology.

In recent years, immunotherapy has achieved great success in the field of tumor immunotherapy [4].

CD8+ T cells play a central role in tumor immunity and are a decisive factor in the treatment effect and prognosis of cancer patients [5].

Although extensive research has been conducted on MDM2 and p53 signaling pathways in tumor cells, does the signaling pathway regulate CD8+ cell-mediated tumor immunity? Whether targeting MDM2 and p53 signaling pathways can change the host immune system and affect the targeted efficacy , Still unclear.

On March 25, 2021, the team of Professor Weiping Zou from the University of Michigan (Dr.
Jiajia Zhou is the first author) published an article The ubiquitin ligase MDM2 sustains STAT5 stability to control T cell-mediated anti-tumor immunity in Nature Immunology, Shao Wang, University of Michigan Professor Moe is a key partner in this subject.

This study reveals that the MDM2-STAT5 signaling pathway regulates the immunological mechanism mediated by T cells.
This work provides new ideas for the development of immune drugs targeting MDM2-p53 and the determination of their tumor treatment indications.

In this study, the researchers first identified the high expression of MDM2 in activated human and mouse CD8+ T cells.

In order to explore how MDM2 regulates T cell functions, the researchers constructed a MDM2-specific T cell conditional knockout mouse model.

Compared with wild-type mice, MDM2 knockout mice have faster tumor growth.

Further studies have shown that in MDM2 knockout mice, a large number of infiltrating CD8+ T cells undergo apoptosis, which in turn affects the number of CD8+ T cells.

In addition, the researchers also constructed a p53-specific T cell conditional knockout mouse model.

In vivo and in vitro experiments have shown that MDM2 regulates the survival and function of CD8+ T cells independent of p53 activity.

In order to explore the molecular mechanism of MDM2 regulating the function of CD8+ T cells, researchers found that MDM2 specifically regulates the stability of STAT5 through molecular biology techniques in multiple cell lines.

In view of the protein degradation function of the ubiquitin E3 ligase of MDM2, it is completely unexpected that MDM2 can stabilize the STAT5 protein.

Studies have shown that the stability of murine fibroblasts and human mesenchymal stromal cells STAT5 is regulated by ubiquitin E3 ligase c-Cbl [6-7].

Further studies have shown that knocking down the expression of MDM2 does not affect the expression of c-Cbl, and knocking down c-Cbl does not affect the expression of MDM2.

Biochemical experiments show that MDM2 prevents the binding of c-Cbl and STAT5, reduces c-Cbl-mediated degradation of STAT5, and enhances the stability of STAT5 in tumor-infiltrating CD8+ T cells (Figure 1).

Given that MDM2 can prevent the degradation of STAT5 in T cells and contribute to T cell-mediated anti-tumor immunity, enhancing the expression of MDM2 protein in T cells may trigger T cell-mediated anti-tumor immunity and treat cancer.

Researchers found that APG-115, an effective small molecule drug targeting the MDM2-p53 interaction [8], promotes the expression of p53 and MDM2 in mouse and human T cells.

Interestingly, treatment with APG-115 can inhibit tumor growth in mice with multiple tumor types.

Further studies have found that the anti-tumor effect of APG-115 is accompanied by an increase in the survival and function of CD8 + T cells in the tumor microenvironment, and is dependent on CD8 + T cells.

The anti-tumor effect of APG-115 has nothing to do with the genetic status of tumor p53, but it completely depends on the host CD8 + T cells and the presence of p53 and MDM2 in CD8 + T cells.

Clinically, the abundance of MDM2 is related to the T cell function and IFNγ signal of cancer patients.

Targeting the p53-MDM2 interaction in vivo can increase p53 and MDM2 in T cells, enhance T cell-mediated anti-tumor immunity, and coordinate immunotherapy.

In addition, the research can expand the effective development and selection of MDM2 targeted drugs.

MDM2 in T cells can be used as a patient selection indicator for clinical trials of MDM2 targeted drugs (including those in clinical development for tumor p53-MDM2 inhibitors).

It is worth mentioning that, given that inhibiting MDM2 in vivo may inevitably target MDM2 in T cells, this study questioned whether inhibiting tumor MDM2 is an effective anti-cancer method.

Excitingly, drugs that target the interaction of MDM2 and p53 can increase MDM2 in T cells and induce anti-tumor immunity.

The efficacy of these drugs does not depend on the tumor p53 status.

Therefore, the disease indications are extended to tumors with p53 mutations.

Professor Wang Shaomeng is the designer of APG-115.

APG-115 was authorized by the University of Michigan to Yasheng Pharmaceutical.

Has entered clinical trial.

Figure 1.
MDM2 prevents c-Cbl from binding to STAT5, reduces c-cbl-mediated degradation of STAT5 and supports CD8+ T cell-mediated tumor immunity.

In summary, this study reveals that MDM2 regulates the stability of STAT5 in CD8 + T cells on the one hand, which is essential for effective anti-tumor immunity; on the other hand, from a clinical perspective, it targets the interaction of p53 and MDM2 The small molecule drug APG115 can induce the expression of MDM2 in CD8+ T cells, stabilize STAT5, enhance T cell function, and have a synergistic effect with immunotherapy, regardless of the status of tumor p53.

Finally, this study may provide a reference for finding MDM2 targeted drugs and help carry out related clinical trials.

Part of the recent work of Zou Weiping’s research group is attached: 1.
Cancer Discovery | Zou Weiping’s group reveals the mechanism of optic neuroprotein loss mediated immune escape in colorectal cancer 2.
Cancer Cell | Zou Weiping’s group reveals that the new phagocytic signal node protein participates in immunotherapy tolerance 3.
Nat Med | Zou Weiping's group reveals the mechanism by which cancer liver metastasis affects the effect of immunotherapy 4.
Nature | Zou Weiping's team reveals that tumor cells can take up methionine to affect T cell histone methylation and function 5.
Nature | Zou Weiping's group reveals that iron death is involved The role of tumor immunotherapy 6.
Submitted by Fang Jingyuan Group and other Cells to reveal the important molecular mechanism of intestinal microbes and tumor chemotherapy toleranceBioArt recommends the original link: -021-00888-3‍ Plate maker: Eleven references [1] Wade, M.
, Li, YC & Wahl, GM MDM2, MDMX and p53 in oncogenesis and cancer therapy.
Nat Rev Cancer 13, 83-96 (2013) 【2】Shangary, S.
& Wang, S.
Small-molecule inhibitors of the MDM2-p53 protein-protein interaction to reactivate p53 function: a novel approach for cancer therapy.
Annu Rev Pharmacol Toxicol 49, 223-241 (2009).
[3] Karni-Schmidt, O.
, Lokshin, M.
& Prives, C.
The Roles of MDM2 and MDMX in Cancer.
Annu Rev Pathol 11, 617-644 (2016).
[4] Zou, W.
, Wolchok, JD & Chen, L.
PD-L1 (B7-H1) and PD-1 pathway blockade for cancer therapy: Mechanisms, response biomarkers, and combinations.
Sci Transl Med 8, 328rv324 (2016).
[5] Topalian, SL, Drake, CG & Pardoll, DM Immune checkpoint blockade: a common denominator approach to cancer therapy.
Cancer Cell 27, 450-461 (2015).
[6] Goh, EL, Zhu, T.
, Leong, WY & Lobie, PE c-Cbl is a negative regulator of GH-stimulated STAT5-mediated transcription.
Endocrinology 143, 3590-3603 (2002).
[7] Dieudonne, FX et al.
Promotion of osteoblast differentiation in mesenchymal cells through Cbl-mediated control of STAT5 activity.
Stem Cells 31, 1340-1349 (2013).
【8】Aguilar, A.
et al.
Discovery of 4-((3'R,4'S,5'R)-6''-Chloro-4'-(3-chloro-2-fluorophenyl)- 1'-ethyl-2''-oxodispiro[ cyclohexane-1,2'-pyrrolidine-3',3''-indoline]-5'-carboxamido)bicyclo[2.
2.
2]octane -1-carboxylic Acid (AA-115/APG-115): A Potent and Orally Active Murine Double Minute 2 (MDM2) Inhibitor in Clinical Development.
J Med Chem 60, 2819-2839 (2017) Reprinting instructions [Non-original articles] The copyright of this article belongs to the author of the article.
Personal forwarding and sharing are welcome.
Reprinting is prohibited without permission.
The author has all legal rights, and offenders must be investigated.