IL-17–induced HIF1α drives resistance to anti–PD-L1 via fibroblast-mediated immune exclusion

Chen, Xing; Zhao, Junjie; Herjan, Tomasz; Hong, Lingzi; Liao, Yun; Liu, Caini; Vasu, K.I.; Wang, Han; Thompson, Austin; Fox, Paul L.; Gastman, Brian; Li, Xiao; Li, Xiaoxia

doi:10.1084/jem.20210693

Cited by 26 publications

(19 citation statements)

References 62 publications

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“…The genes that have been differentially modulated are associated with pathways, including p53 signaling pathway, PI3K-Akt signaling pathway, HIF-1 signaling pathway, Hippo signaling pathway, TNF signaling pathway, chemokine ligand 12 signaling pathway, and cytokine production; moreover, retinol metabolism, carbon metabolism, glycolysis, gluconeogenesis, and primary bile acid biosynthesis related with cancer also changed in the two clusters. Previous studies had showed that p53 signaling pathway, PI3K-Akt signaling pathway, HIF-1 signaling pathway are important pathways involved in tumor development and metastasis ( 22 , 23 ). Additionally, glycolysis, gluconeogenesis, and bile acid biosynthesis also play an important role in the tumor progression ( 24 – 26 ).…”

Section: Discussionmentioning

confidence: 99%

Identification of copper metabolism and cuproptosis-related subtypes for predicting prognosis tumor microenvironment and drug candidates in hepatocellular carcinoma

et al. 2022

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Copper (Cu) is an essential element of organisms, which can affect the survival of cells. However, the role of copper metabolism and cuproptosis on hepatic carcinoma is still unclear. In this study, the TCGA database was used as the test set, and the ICGC database and self-built database were used as the validation set. We screened out a class of copper metabolism and cuproptosis-related genes (CMCRGs) that could influence hepatic carcinoma prognosis by survival analysis and differential comparison. Based on CMCRGs, patients were divided into two subtypes by cluster analysis. The C2 subtype was defined as the high copper related subtype, while the C1 subtype was defied as the low copper related subtype. At the clinical level, compared with the C1 subtype, the C2 subtype had higher grade pathological features, risk scores, and worse survival. In addition, the immune response and metabolic status also differed between C1 and C2. Specifically, C2 subtype had a higher proportion of immune cell composition and highly expressed immune checkpoint genes. C2 subtype had a higher TIDE score with a higher proportion of tumor immune dysfunction and exclusion. At the molecular level, the C2 subtype had a higher frequency of driver gene mutations (TP53 and OBSCN). Mechanistically, the single nucleotide polymorphisms of C2 subtype had a very strong transcriptional strand bias for C>A mutations. Copy number variations in the C2 subtype were characterized by LOXL3 CNV gain, which also showed high association with PDCD1/CTLA4. Finally, drug sensitivity responsiveness was assessed in both subtypes. C2 subtype had lower IC50 values for targeted and chemotherapeutic agents (sorafenib, imatinib and methotrexate, etc.). Thus, CMCRGs related subtypes showed poor response to immunotherapy and better responsiveness to targeted agents, and the results might provide a reference for precision treatment of hepatic carcinoma.

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Section: Discussionmentioning

confidence: 99%

Identification of copper metabolism and cuproptosis-related subtypes for predicting prognosis tumor microenvironment and drug candidates in hepatocellular carcinoma

et al. 2022

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“…IL-17A is a cytokine with multifunctional properties. It mediates numerous pathophysiological processes such as in ammatory responses [29,30], tumor immunity [31][32][33], and bone remodeling [34,35] by acting on different types of downstream cells and prompting the synthesis and secretion of various proin ammatory mediators, chemokines, and proliferative cytokines. In the present study, we found for the rst time that IL-17A has a role in enhancing osteogenic differentiation of LFCs.…”

Section: Discussionmentioning

confidence: 99%

Interleukin-17A promotes proliferation and osteogenic differentiation of human ligamentum flavum cells through regulation of β-catenin nuclear translocation

Lin

Jiang

Xiang

et al. 2022

Preprint

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Thoracic ossification of the ligamentum flavum (TOLF) is the leading cause of thoracic spinal stenosis with no specifc treatment available. IL-17A has received widespread attention for its key contribution in the regulation of bone metabolism and heterotopic ossification. However, it is unclear whether IL-17A is involved in TOLF. Our results showed that IL-17A expression was elevated in ossified ligamentum flavum tissue compared to normal ligamentum flavum. In in vitro experiments, IL-17A stimulation promoted the proliferation and osteogenic differentiation of ligamentum flavum cells (LFCs) derived from TOLF patients. Mechanistically, we found that IL-17A stimulation promoted nuclear translocation of β-catenin, whereas silencing of β-catenin attenuated IL-17A-induced proliferation and osteogenic differentiation of LFCs. Furthermore, co-culture of T helper 17 (Th17) cells with LFCs showed that IL-17A secreted by Th17 cells significantly enhanced the accumulation of β-catenin in the nucleus, as well as the proliferation and osteogenic differentiation of LFCs. However, these effects were markedly attenuated after the neutralization of IL-17A. Our study demonstrates that IL-17A secreted by Th17 cells in the lesion microenvironment may be involved in TOLF by regulating nuclear translocation of β-catenin to promote proliferation and osteogenic differentiation of LFCs. This study helps to elucidate the pathological mechanism of TOLF and suggests the possibility of IL-17A as a potential target for the prevention and treatment of TOLF.

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“…IL-17 is a prominent cytokine that plays a critical role in tumor progression and immune response ( 262 – 265 ). It is linked with poor prognosis and drives resistance in solid tumors ( 266 , 267 ) and also acts as a prognostic biomarker in different types of human cancers ( 268 , 269 ). Recently, Wu et al.…”

Section: Strategies To Target Neutrophilsmentioning

confidence: 99%

Neutrophils: Musketeers against immunotherapy

et al. 2022

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Neutrophils, the most copious leukocytes in human blood, play a critical role in tumorigenesis, cancer progression, and immune suppression. Recently, neutrophils have attracted the attention of researchers, immunologists, and oncologists because of their potential role in orchestrating immune evasion in human diseases including cancer, which has led to a hot debate redefining the contribution of neutrophils in tumor progression and immunity. To make this debate fruitful, this review seeks to provide a recent update about the contribution of neutrophils in immune suppression and tumor progression. Here, we first described the molecular pathways through which neutrophils aid in cancer progression and orchestrate immune suppression/evasion. Later, we summarized the underlying molecular mechanisms of neutrophil-mediated therapy resistance and highlighted various approaches through which neutrophil antagonism may heighten the efficacy of the immune checkpoint blockade therapy. Finally, we have highlighted several unsolved questions and hope that answering these questions will provide a new avenue toward immunotherapy revolution.

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IL-17–induced HIF1α drives resistance to anti–PD-L1 via fibroblast-mediated immune exclusion

Cited by 26 publications

References 62 publications

Identification of copper metabolism and cuproptosis-related subtypes for predicting prognosis tumor microenvironment and drug candidates in hepatocellular carcinoma

Identification of copper metabolism and cuproptosis-related subtypes for predicting prognosis tumor microenvironment and drug candidates in hepatocellular carcinoma

Interleukin-17A promotes proliferation and osteogenic differentiation of human ligamentum flavum cells through regulation of β-catenin nuclear translocation

Neutrophils: Musketeers against immunotherapy

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