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Review
. 2024 Sep 3;16(17):3069.
doi: 10.3390/cancers16173069.

TP53 Mutation-Mediated Immune Evasion in Cancer: Mechanisms and Therapeutic Implications

Chuqi Wang  1 , Jordan Yong Ming Tan  1 , Nishtha Chitkara  2 , Shruti Bhatt  1
Affiliations
Review

TP53 Mutation-Mediated Immune Evasion in Cancer: Mechanisms and Therapeutic Implications

Chuqi Wang et al. Cancers (Basel). .

Abstract

Mutation in p53 is the most frequent event in cancer development and a leading cause of cancer therapy resistance due to evasion of the apoptosis cascade. Beyond chemotherapies and radiation therapies, growing evidence indicates that p53-mutant tumors are resistant to a broad range of immune-based therapies, such as immune checkpoint inhibitors, chimeric antigen receptor (CAR) T, and hematopoietic stem cell transplantation (HSCT). This highlights the role of p53 mutations in driving immune evasion of tumor cells. In this review, we first summarize recent studies revealing mechanisms by which p53-mutant tumors evade immune surveillance from T cells, natural killer (NK) cells, and macrophages. We then review how these mutant tumor cells reshape the tumor microenvironment (TME), modulating bystander cells such as macrophages, neutrophils, and regulatory T (Treg) cells to foster immunosuppression. Additionally, we review clinical observations indicative of immune evasion associated with p53 loss or mutations. Finally, we discuss therapeutic strategies to enhance immune response in p53 wild-type (WT) or mutant tumors.

Keywords: immune evasion; immunotherapy; mouse double minute 2; p53; p53 mutation.

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Conflict of interest statement

The authors declare no conflicts of interest.

Figures

Figure 1
Figure 1
Molecular functions of p53. p53 is activated by cytotoxic stressors such as DNA damage, hypoxia, nutrient deficiency, oxidative stress, or oncogene activation via the inhibition of the MDM-2 pathway. p53 acts as a tumor suppressor, ensuring genomic stability within the cell by inducing cell cycle arrest, DNA repair mechanisms, senescence, or apoptosis, which consequently leads to effective tumor suppression.
Figure 2
Figure 2
Mechanisms of immune evasion mediated by p53 mutation or deletion. (a) p53-deficient tumor cells employ multiple strategies to evade T cell-mediated killing, including downregulation of MHC Class I and II molecules, loss of TRAIL receptors, and upregulation of PD-L1 expression. (b) p53 mutations hinder the anti-tumor functions of the innate immunity. p53-mutant cells are evasive to NK cells by downregulation of NK-activating ligands (e.g., NKG2D ligands, PVR, and Nectin-2) and suppressing the cGAS-STING pathway. Additionally, p53 mutation leads to reduced expression of pro-apoptotic protein (NOXA/BAX/PUMA), which makes the tumor cells resistant to NK-mediated apoptosis. p53-mutant cells also release extracellular vesicles expressing PD-L1 to inhibit phagocytosis by macrophages, contributing to the immune evasion. Alterations in cancer cell secretome (e.g., reduced IL-15 and increased TGF-β) further suppress overall immune response.
Figure 3
Figure 3
p53-mutant/deficient tumor cells reshape the TME to cause immunosuppression. p53-mutant tumor cells can release cytokines and exosomes to reprogram macrophages into immunosuppressive phenotypes. These mutant tumor cells can also recruit neutrophils and Tregs into the TME to suppress T cell functions.
Figure 4
Figure 4
Strategies to enhance immune response against p53-WT and -mutant tumors. (a) MDM2 inhibitors can synergize with immunotherapies, such as ICB, immune cell adoptive transfer, and HSCT, by increasing the immunogenicity of tumor cells and polarizing macrophages in the TME into the proinflammatory M1 phenotype. (b) STING agonists have the potential to boost anti-tumor immunity against p53-mutant tumors and sensitize them to immunotherapies. (c) Novel p53-restoring small molecules and gene therapies delivering WT p53 can restore the function of mutant p53, making tumors susceptible to immune attack. (d) Immune-based therapies, such as TIL, TCR-T, and therapeutic antibodies, can kill p53-mutant tumor cells by recognizing mutant p53 peptides presented by MHC I on the tumor surface.
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References

    1. Ge T., Gu X., Jia R., Ge S., Chai P., Zhuang A., Fan X. Crosstalk between metabolic reprogramming and epigenetics in cancer: Updates on mechanisms and therapeutic opportunities. Cancer Commun. 2022;42:1049–1082. doi: 10.1002/cac2.12374. - DOI - PMC - PubMed
    1. Zhang Y., Xiong S., Liu B., Pant V., Celii F., Chau G., Elizondo-Fraire A.C., Yang P., You M.J., El-Naggar A.K., et al. Somatic Trp53 mutations differentially drive breast cancer and evolution of metastases. Nat. Commun. 2018;9:3953. doi: 10.1038/s41467-018-06146-9. - DOI - PMC - PubMed
    1. Olivier M., Langerød A., Carrieri P., Bergh J., Klaar S., Eyfjord J., Theillet C., Rodriguez C., Lidereau R., BièChe I., et al. The clinical value of somatic TP53 gene mutations in 1,794 patients with breast cancer. Clin. Cancer Res. 2006;12:1157–1167. doi: 10.1158/1078-0432.CCR-05-1029. - DOI - PubMed
    1. Lane D.P. p53, guardian of the genome. Nature. 1992;358:15–16. doi: 10.1038/358015a0. - DOI - PubMed
    1. Vogelstein B., Lane D., Levine A.J. Surfing the p53 network. Nature. 2000;408:307–310. doi: 10.1038/35042675. - DOI - PubMed

Grants and funding

S.B. acknowledges funding from the Paris-NUS Call for Proposals 2024 (ANR-18-IDEX-0001). C.W. acknowledges support from the Paris-NUS call for PhD mobility 2024 (ANR-18-IDEX-0001).

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