The p53 effector Perp mediates the persistence of CD4+ effector memory T-cell undergoing lymphopenia-induced proliferation

Zhou, Yan; Leng, Xiao; Mo, Chunfen; Zou, Qiang; Liu, Yang; Wang, Yantang

doi:10.1016/j.imlet.2020.05.001

Cited by 4 publications

(2 citation statements)

References 33 publications

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“…Additionally, the quantity of CD4+ memory T-cells was less in missense mutant p53 samples compared with that in wild-type p53 samples. The crucial role of Perp, a p53 pro-apoptotic target, in mediating the persistence of CD4+ effector memory T-cell undergoing lymphopenia-induced proliferation 45 . It showed that CD4 memory resting T cells and M1 macrophages may be correlated with the TMRS (tumor metabolic risk score), which corresponded to immunoediting in p53 mutant lung adenocarcinoma patients 46 .…”

Section: Resultsmentioning

confidence: 99%

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

Liu¹,

Jiang²,

Guo³

et al. 2022

Int. J. Biol. Sci.

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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.

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Section: Resultsmentioning

confidence: 99%

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

Liu¹,

Jiang²,

Guo³

et al. 2022

Int. J. Biol. Sci.

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“…Meanwhile, the TCR repertoire diversity was decreased, and the increasingly expanded clonotypes of CD4 positive Tem occurred in the "High-risk" group. In the prior studies, the overwhelming expansion of CD4 positive Tem was found in the state of lymphopenia (49,50). As the peripheral blood is a limited pool to restore T cells, the expansion clonotype of one T cell subtype may result in suppression of the others (51,52).…”

Section: Discussionmentioning

confidence: 96%

Prognostic Significance of NLR About NETosis and Lymphocytes Perturbations in Localized Renal Cell Carcinoma With Tumor Thrombus

et al. 2021

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BackgroundNon-metastatic renal cell carcinoma (RCC) with tumor thrombus showed a greater tendency for developing metastases after surgery. Early identification of patients with high risk of poor prognosis is especially important to explore adjuvant treatment of improving outcomes. Neutrophil-to-lymphocyte ratio (NLR) was a systemic inflammation marker and outcome predictor in RCC, reflecting the chaos in systemic immune status in cancer as myeloid cell expansion and lymphatic cell suppression. Neutrophil extracellular traps (NET) formation (NETosis) is the process of neutrophils generating an extracellular DNA net-like structure. NETosis in tumor was demonstrated to conduce to the subsequent metastases of tumor. However, the role of NLR for systemic immune status and tumor local immune infiltration, especially for neutrophil-associated NETs, in non-metastatic RCC with thrombus remains unclear.Patients and MethodsIn our clinical cohort, we enrolled the clinical, pathologic, and preoperative laboratory parameters of 214 RCC patients with tumor thrombus who were treated surgically. The clinical endpoint was defined as cancer-specific survival (CSS). In our basic research cohort, RNA-seq, TCR-seq, and scRNA-seq data were analyzed. Patients who reached the endpoint as recurrence-free survival (RFS) were defined as the “High-risk” group. Otherwise, they were separated into the “Low-risk” group.ResultsIn the clinical cohort, NLR≥4 was an independent risk factor for 203 localized RCC with tumor thrombus. In the basic research cohort, tumor thrombi were separated into NETosis-thrombi belonging to the “High-risk” group and non-NETosis-thrombi to the “Low-risk” group. NETs induced by tumor-derived G-CSF in tumor thrombus has a mechanistic role in unfavorable prognosis. Besides, NETs-score from single sample GSEA (ssGSEA) algorithm was an independent prognostic factor validated in the TCGA data. Apart from the neutrophils-associated NETosis, systemic immune perturbations of lymphocytes occurred in the “High-risk” group, represented with decreased TCR diversity and increasingly high proportion of CD4-positive effector memory T (Tem) cells, which indirectly represented the state of lymphopenia.ConclusionsOur findings firstly demonstrated that neutrophils-associated NETosis and systemic lymphocytes perturbations were considered as tumor progression in patients of localized RCC with tumor thrombus, which reflected NLR≥4 as an independent risk factor for patients.

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Targeting the Viral Entry Pathways through Repurposed Drugs in Sars-Cov-2 Infection

Mulchandani

Palai

Bhosale

et al. 2023

Drug Repurposing Against SARS-CoV-2

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SARS-CoV-2 belongs to the family coronviradae and the disease caused by this virus is known as COVID-19. Viral entry into the cell is favored by spike glycoprotein, which interacts with Angiotensin-converting-enzyme-2 (ACE-2). Moreover, proteins such as Transmembrane Protease Serine-2 (TMPRSS-2), are responsible for viral fusion with cellular epithelium. Traditional drug discovery methods and their development process are time-consuming as well as expensive. Thus, there is a need for a method that can overcome such drawbacks. Drug repurposing is an approach in which we can use an existing drug that is already being used for another disease. The repurposing of drugs is also known as repositioning. It is the process that identifies new therapeutic use for existing or available drugs. Hydroxychloroquine inhibits ACE-2 glycosylation virus entry to the host body; arbidol prevents fusion of viral lipid shell with cell membrane hence restricting contact and penetration of virus. Drug repurposing could be a successful strategy for the treatment of sporadic, neglected diseases, difficult-to-treat diseases, and the current pandemic situation, i.e., COVID-19. However, there is no denying the fact that there are several limitations to this approach.

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The p53 effector Perp mediates the persistence of CD4+ effector memory T-cell undergoing lymphopenia-induced proliferation

Cited by 4 publications

References 33 publications

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

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

Prognostic Significance of NLR About NETosis and Lymphocytes Perturbations in Localized Renal Cell Carcinoma With Tumor Thrombus

Targeting the Viral Entry Pathways through Repurposed Drugs in Sars-Cov-2 Infection

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