PLCγ1/PKCθ Downstream Signaling Controls Cutaneous T-Cell Lymphoma Development and Progression

García-Díaz, Nuria; Casar, Berta; Alonso‐Alonso, Ruth; Quevedo, Laura; Rodríguez, Marta; Ruso-Julve, Fulgencio; Esteve‐Codina, Anna; Gut, Marta; Gru, Alejandro A.; González‐Vela, M. Carmen; Gut, Ivo; Rodríguez‐Peralto, José Luis; Varela, Ignacio; Ortiz‐Romero, Pablo L.; Piris, M A; Vaqué, José P.

doi:10.1016/j.jid.2021.09.024

Cited by 5 publications

(3 citation statements)

References 48 publications

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“…The PKCθ/NF-κB pathway is as a critical promoter of T cell lymphomagenesis. A recent study revealed that PKCθ promoted CTCL development and progression in a chicken embryo xenograft ( 42 ), supporting the idea that PRKCQ functions as a potent oncogene in CTCLs. In this case, PRKCQ amplification led to PKCθ overexpression and constitutional TCR activation in malignant T cells.…”

Section: Discussionmentioning

confidence: 67%

Hyperprogression of cutaneous T cell lymphoma after anti–PD-1 treatment

Gao¹,

Hu²,

Li³

et al. 2023

JCI Insight

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BACKGROUND. Immune checkpoint blockade is an emerging treatment for T cell non-Hodgkin lymphoma (T-NHL), but some T-NHL patients have experienced hyperprogression with undetermined mechanisms upon anti-PD-1 therapy.METHODS. Single-cell RNA sequencing, whole-genome sequencing, whole-exome sequencing, and functional assays were performed on primary malignant T cells from a patient with advanced cutaneous T cell lymphoma, who experienced hyperprogression upon anti-PD-1 treatment.RESULTS. The patient was enrolled in a clinical trial of anti-PD-1 therapy and experienced disease hyperprogression. Single-cell RNA sequencing revealed that PD-1 blockade elicited a remarkable activation and proliferation of the CD4+ malignant T cells, which showed functional PD-1 expression and an exhausted status. Further analyses identified somatic amplification of PRKCQ in the malignant T cells. PRKCQ encodes PKCθ, a key player in the T cell activation/NF-kB pathway. PRKCQ amplification led to high expressions of PKCθ and p-PKCθ (T538) on the malignant T cells, resulting in an oncogenic activation of the T cell receptor (TCR) signaling pathway. PD-1 blockade in this patient released this signaling, de-repressed the proliferation of malignant T cells, and resulted in disease hyperprogression. 30CONCLUSIONS. Our study provides real-world clinical evidence that PD-1 acts as a tumor suppressor for malignant T cells with oncogenic TCR activation. TRIAL REGISTRATION. ClinicalTrials.gov (NCT03809767).

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Section: Discussionmentioning

confidence: 67%

Hyperprogression of cutaneous T cell lymphoma after anti–PD-1 treatment

Gao¹,

Hu²,

Li³

et al. 2023

JCI Insight

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“…Upon T-cell activation, as a phospholipase, PLCG1 can cleave phosphatidylinositol 4,5-diphosphate in the plasma membrane into two second messengers: inositol 1,4,5 triphosphate and diacylglycerol. Inositol 1,4,5-triphosphate causes calcium release from the endoplasmic reticulum, increases the intracellular calcium concentration and activates NFAT, while diacylglycerol activates specific isoforms of protein kinase C (PKC) [ 54 , 55 ]. Recent bioinformatics analysis identified that PLCG1 was frequently highly expressed and mutated in various cancers and was involved in tumorigenesis as an oncogene [ 56 ].…”

Section: Discussionmentioning

confidence: 99%

“…The PLCG1-mediated signaling pathway also regulated tumor metastasis. The PLCG1/PKCθ axis accelerated STAT3 activation and promoted the proliferation and survival of cutaneous T-cell lymphoma cells [ 55 ]. These results have highlighted the important role of these PRGs in immunity and oncogenesis.…”

Section: Discussionmentioning

confidence: 99%

A novel risk score model based on pyroptosis-related genes for predicting survival and immunogenic landscape in hepatocellular carcinoma

Wang

Zhang

Shang

et al. 2023

Aging

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Background: Hepatocellular carcinoma (HCC) is the third leading cause of cancer worldwide, with high incidence and mortality. Pyroptosis, a form of inflammatory-regulated cell death, is closely associated with oncogenesis. Methods: Expression profiles of HCC were downloaded from the TCGA database and validated using the ICGC and GEO databases. Consensus clustering analysis was used to determine distinct clusters. The pyroptosis-related genes (PRGs) included in the pyroptosis-related signature were selected by univariate Cox regression and LASSO regression analysis. Kaplan-Meier and receiver operating characteristic (ROC) analyses were performed to estimate the prognostic potential of the model. The characteristics of infiltration of immune cells between different groups of HCC were explored. Results: Two independent clusters were identified according to PRG expression. Cluster 2 showed upregulated expression, poor prognosis, increased immune cell infiltration and worse immunotherapy response than cluster 1. A prognostic risk signature consisting of five genes (GSDME, NOD1, PLCG1, NLRP6 and NLRC4) was identified. In the high-risk score group, HCC patients showed decreased survival rates. In particular, multiple clinicopathological characteristics and immune cell infiltration were significantly associated with the risk score. Notably, the 5 PRGs in the risk score have been implicated in carcinogenesis, immunological pathways and drug sensitivity. Conclusions: A prognostic signature comprising five PRGs can be used as a potential prognostic factor for HCC. The PRG-related signature provides an in-depth understanding of the association between pyroptosis and chemotherapy or immunotherapy for HCC patients.

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