Lck bound to coreceptor is less active than free Lck

Wei, Qianru; Brzostek, Joanna; Sankaran, Shvetha; Casas, Javier; Hew, Lois Shi-Qi; Yap, Jiawei; Xiang, Zhao; Wojciech, Łukasz; Gascoigne, Nicholas R. J.

doi:10.1073/pnas.1913334117

Cited by 41 publications

(48 citation statements)

References 45 publications

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“…Moreover, high expression of CD3E and CD3D gene were reported significantly related to positive OS in CESC ( Wang et al, 2019b ). LCK, also known as lymphocyte-specific protein tyrosine kinase p56, was found as a key molecule in T cell activation by phosphorylating the TCR/CD3 complex to initiate TCR signaling ( Wei et al, 2020 ). Recent studies showed that the improved LCK activity was contributed to improve the efficacy of chimeric antigen receptors (CARs) immunotherapy in cancers ( Gulati et al, 2018 ; Bommhardt et al, 2019 ; Suryadevara et al, 2019 ).…”

Section: Discussionmentioning

confidence: 99%

Exploration of a Robust and Prognostic Immune Related Gene Signature for Cervical Squamous Cell Carcinoma

Zuo

Xiong

Zeng

et al. 2021

Front. Mol. Biosci.

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Background: Cervical squamous cell carcinoma (CESC) is one of the most frequent malignancies in women worldwide. The level of immune cell infiltration and immune-related genes (IRGs) can significantly affect the prognosis and immunotherapy of CESC patients. Thus, this study aimed to identify an immune-related prognostic signature for CESC.Methods: TCGA-CESC cohorts, obtained from TCGA database, were divided into the training group and testing group; while GSE44001 dataset from GEO database was viewed as external validation group. ESTIMATE algorithm was applied to evaluate the infiltration levels of immune cells of CESC patients. IRGs were screened out through weighted gene co-expression network analysis (WGCNA). A multi-gene prognostic signature based on IRGs was constructed using LASSO penalized Cox proportional hazards regression, which was validated through Kaplan–Meier, Cox, and receiver operating characteristic curve (ROC) analyses. The abundance of immune cells was calculated using ssGSEA algorithm in the ImmuCellAI database, and the response to immunotherapy was evaluated using immunophenoscore (IPS) analysis and the TIDE algorithm.Results: In TCGA-CESC cohorts, higher levels of immune cell infiltration were closely associated with better prognoses. Moreover, a prognostic signature was constructed using three IRGs. Based on this given signature, Kaplan–Meier analysis suggested the significant differences in overall survival (OS) and the ROC analysis demonstrated its robust predictive potential for CESC prognosis, further confirmed by internal and external validation. Additionally, multivariate Cox analysis revealed that the three IRGs signature served as an independent prognostic factor for CESC. In the three-IRGs signature low-risk group, the infiltrating immune cells (B cells, CD4/8 + T cells, cytotoxic T cells, macrophages and so on) were much more abundant than that in high-risk group. Ultimately, IPS and TIDE analyses showed that low-risk CESC patients appeared to present with a better response to immunotherapy and a better prognosis than high-risk patients.Conclusion: The present prognostic signature based on three IRGs (CD3E, CD3D, LCK) was not only reliable for survival prediction but efficient to predict the clinical response to immunotherapy for CESC patients, which might assist in guiding more precise individual treatment in the future.

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Section: Discussionmentioning

confidence: 99%

Exploration of a Robust and Prognostic Immune Related Gene Signature for Cervical Squamous Cell Carcinoma

Zuo

Xiong

Zeng

et al. 2021

Front. Mol. Biosci.

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“…And other genes are thought to be closely related to pancreatic cancer, such as LCK 34 . LCK is critical for T cell development and activation, as it is the first kinase to divert TCR signalling 35 . What's more, LCK, CD247, CD27, CD3D, and CD74 were mentioned as upregulated genes in anti-PDL1 treated mice and downregulated genes in inflammatory breast cancer with PDL1 overexpression 36,37 .…”

Section: Discussionmentioning

confidence: 99%

Transcriptome analysis of the procession from chronic pancreatitis to pancreatic cancer and metastatic pancreatic cancer

Huang

Wang

et al. 2021

Sci Rep

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Exploring the underlying mechanisms of cancer development is useful for cancer treatment. In this paper, we analyzed the transcriptome profiles from the human normal pancreas, pancreatitis, pancreatic cancer and metastatic pancreatic cancer to study the intricate associations among pancreatic cancer progression. We clustered the transcriptome data, and analyzed the differential expressed genes. WGCNA was applied to construct co-expression networks and detect important modules. Importantly we selected the module in a different way. As the pancreatic disease deteriorates, the number of differentially expressed genes increases. The gene networks of T cells and interferon are upregulated in stages. In conclusion, the network-based study provides gradually activated gene networks in the disease progression of pancreatitis, pancreatic cancer, and metastatic pancreatic cancer. It may contribute to the rational design of anti-cancer drugs.

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“…CD4 dwell time on pMHCII is proportional, yet faster, to TCR dwell time, suggesting that TCR:pMHCII interaction kinetics would directly affect the duration that CD4 molecules cycle through the immunological synapse in a processive-like manner ( 88 ). Additionally, compared to coreceptor-bound Lck, CD4-free Lck is phosphorylated more at its Y394 activation site, with higher kinase activity and mobility ( 81 ); thus, it may be that if CD4-free Lck is prevented from interacting with the immunological synapse, activation may be reduced. TCR-pMHCII interactions are highly ordered and uniform, increasing the likelihood that the spatial relationship between Lck and the ITAMs of the TCR-SCS or flTCRs are consistent.…”

Section: Discussionmentioning

confidence: 99%

CD4 Inhibits Helper T Cell Activation at Lower Affinity Threshold for Full-Length T Cell Receptors Than Single Chain Signaling Constructs

Johnson¹,

Magoffin²,

Myers³

et al. 2021

Front. Immunol.

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CD4+ T cells are crucial for effective repression and elimination of cancer cells. Despite a paucity of CD4+ T cell receptor (TCR) clinical studies, CD4+ T cells are primed to become important therapeutics as they help circumvent tumor antigen escape and guide multifactorial immune responses. However, because CD8+ T cells directly kill tumor cells, most research has focused on the attributes of CD8+ TCRs. Less is known about how TCR affinity and CD4 expression affect CD4+ T cell activation in full length TCR (flTCR) and TCR single chain signaling (TCR-SCS) formats. Here, we generated an affinity panel of TCRs from CD4+ T cells and expressed them in flTCR and three TCR-SCS formats modeled after chimeric antigen receptors (CARs) to understand the contributions of TCR-pMHCII affinity, TCR format, and coreceptor CD4 interactions on CD4+ T cell activation. Strikingly, the coreceptor CD4 inhibited intermediate and high affinity TCR-construct activation by Lck-dependent and -independent mechanisms. These inhibition mechanisms had unique affinity thresholds dependent on the TCR format. Intracellular construct formats affected the tetramer staining for each TCR as well as IL-2 production. IL-2 production was promoted by increased TCR-pMHCII affinity and the flTCR format. Thus, CD4+ T cell therapy development should consider TCR affinity, CD4 expression, and construct format.

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Lck bound to coreceptor is less active than free Lck

Cited by 41 publications

References 45 publications

Exploration of a Robust and Prognostic Immune Related Gene Signature for Cervical Squamous Cell Carcinoma

Exploration of a Robust and Prognostic Immune Related Gene Signature for Cervical Squamous Cell Carcinoma

Transcriptome analysis of the procession from chronic pancreatitis to pancreatic cancer and metastatic pancreatic cancer

CD4 Inhibits Helper T Cell Activation at Lower Affinity Threshold for Full-Length T Cell Receptors Than Single Chain Signaling Constructs

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