TOX correlates with prognosis, immune infiltration, and T cells exhaustion in lung adenocarcinoma

Guo, Longbin; Li, Xuanzi; Liu, Rongping; Chen, Yulei; Ren, Chen; Du, Shasha

doi:10.1002/cam4.3324

Cited by 41 publications

(37 citation statements)

References 48 publications

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“…The tumor microenvironment, especially the immune microenvironment, constitutes a vital element of tumor biology. Increasing evidence has revealed its clinicopathological significance in predicting outcomes and therapeutic efficacy ( 13 , 14 ). The infiltration of TAMs facilitates the progression of tumors ( 15 , 16 ).…”

Section: Discussionmentioning

confidence: 99%

HILPDA Is a Prognostic Biomarker and Correlates With Macrophage Infiltration in Pan-Cancer

et al. 2021

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Background: The protein hypoxia-inducible lipid droplet-associated (HILPDA) is differentially expressed in various tumors. However, its role and correlation with immune cell infiltration in most tumors remain unclear.Methods: HILPDA expression was analyzed in pan-cancer data from The Cancer Genome Atlas (TCGA) database. The influence of HILPDA in clinical prognosis was evaluated using clinical survival data from TCGA. Enrichment analysis of HILPDA was conducted using the R package “clusterProfiler.” We downloaded the immune cell infiltration score of TCGA samples from published articles and analyzed the correlation between the magnitude of immune cell infiltration and HILPDA expression.Results: HILPDA was highly expressed and associated with worse overall survival, disease-specific survival, and progression-free interval in most tumor types. In addition, HILPDA expression was significantly associated with the glycolysis pathway and infiltration of immune cells. Tumor-associated macrophage (TAM) infiltration increased in tissues with high HILPDA expression in most tumor types. Immunosuppressive genes, such as PD-L1, PD-1, TGFB1, and TGFBR1 were positively correlated with HILPDA.Conclusions: Our study suggests that HILPDA is a marker of poor prognosis. High HILPDA may contribute to TAM infiltration and be associated with tumor immunosuppression status.

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Section: Discussionmentioning

confidence: 99%

HILPDA Is a Prognostic Biomarker and Correlates With Macrophage Infiltration in Pan-Cancer

et al. 2021

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“…The underlying mechanisms will require further investigation, but one could speculate that the cytokine stimulation is simply not potent enough to further enhance the already ongoing effector or activation program in these two memory T cell subsets. The notion that TOX, but also PD-1 expression can indicate an ongoing effector or activation program in CD8 T cells is important, since PD-1 and (now also) TOX are used as biomarkers of T cell exhaustion (50)(51)(52). Of note, certain features of general activation programs of CD8 Tmem appear to be well conserved and have also been reported as transcriptomic overlap of tissue-resident, recently-activated, and exhausted CD8 T cells (53).…”

Section: Discussionmentioning

confidence: 99%

Inflammatory signals are sufficient to elicit TOX expression in mouse and human CD8+ T cells

Maurice¹,

Berner²,

Taber³

et al. 2021

JCI Insight

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T cell receptor (TCR) stimulation leads to expression of the transcription factor TOX. Prolonged TCR signaling, such as encountered during chronic infections or in tumors, leads to sustained TOX expression, which is required for the induction of a state of exhaustion or dysfunction. While CD8 memory T cells (Tmem) in mice typically do not express TOX at steady state, some human Tmem express TOX, but appear fully functional. This seeming discrepancy between mouse and human T cells has led to the speculation that TOX is differentially regulated between these species, which could complicate the interpretation of pre-clinical mouse model studies. We report here that similarly to TCR-mediated signals, inflammatory cytokines are also sufficient to increase TOX expression in human and mouse Tmem. Thus, TOX expression is controlled by the environment, which provides an explanation for the different TOX expression patterns encountered in T cells isolated from specific pathogen free laboratory mice versus humans. Finally, we report that TOX is not necessary for cytokine-driven expression of PD-1. Overall, our data highlight that the mechanisms regulating TOX expression are conserved across species and indicate that TOX expression reflects a T cell's activation state, and does not necessarily correlate with T cell dysfunction.

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“…The underlying mechanisms will require further investigation, but one could speculate that the cytokine stimulation is simply not potent enough to further enhance the already ongoing effector or activation program in these two memory T cell subsets. The notion that TOX, but also PD-1 expression can indicate an ongoing effector or activation program in CD8 T cells is important, since PD-1 and (now also) TOX are used as biomarkers of T cell exhaustion 49, 50, 51 . Of note, certain features of general activation programs of CD8 T mem appear to be well conserved and have also been reported as transcriptomic overlap of tissue-resident, recently-activated, and exhausted CD8 T cells 52 .…”

Section: Discussionmentioning

confidence: 99%

Inflammatory signals are sufficient to elicit TOX expression in mouse and human CD8 T cells

Maurice

Berner

Taber

et al. 2021

Preprint

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T cell receptor (TCR) stimulation leads to expression of the transcription factor TOX. Prolonged TCR signaling, such as encountered during chronic infections or in tumors, leads to sustained TOX expression, which induces a state of exhaustion or dysfunction. While CD8 memory T cells (Tmem) in specific pathogen-free laboratory mice typically do not express TOX, functional human Tmem show heterogeneous TOX expression levels. Whether TCR-independent mechanisms can alter TOX expression in human and murine Tmem has not been defined. We report that human and mouse Tmem increase TOX expression following stimulation with inflammatory cytokines IL-12, IL-15, and IL-18. TOX and PD-1 expression patterns often appear to be directly correlated, however, we found that TOX is not necessary for cytokine-driven expression of PD-1. Together, these observations highlight that inflammation is sufficient to alter TOX and PD-1 expression and that the signals regulating TOX expression appear well conserved in human and murine Tmem.

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TOX correlates with prognosis, immune infiltration, and T cells exhaustion in lung adenocarcinoma

Cited by 41 publications

References 48 publications

HILPDA Is a Prognostic Biomarker and Correlates With Macrophage Infiltration in Pan-Cancer

HILPDA Is a Prognostic Biomarker and Correlates With Macrophage Infiltration in Pan-Cancer

Inflammatory signals are sufficient to elicit TOX expression in mouse and human CD8+ T cells

Inflammatory signals are sufficient to elicit TOX expression in mouse and human CD8 T cells

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