Cancer-associated fibroblasts downregulate type I interferon receptor to stimulate intratumoral stromagenesis

Cho, Christina; Mukherjee, Riddhita; Peck, Amy R.; Sun, Yeying; McBrearty, Noreen; Katlinski, Kanstantsin V.; Gui, Jun; Govindaraju, Priya; Puré, Ellen; Rui, Hallgeir; Fuchs, Serge Y.

doi:10.1038/s41388-020-01424-7

Cited by 19 publications

(15 citation statements)

References 39 publications

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“…106 107 A recent study by Cho et al showed that IFNAR1 deficient cancer-associated fibroblasts play a significant role in stromagenesis and contribute to rapid tumor growth. 108 Conversely, when IFNAR1 is intact, conventional therapies can induce IFN-β and lead to induction of HLA-I expression. 109 110 For example, Wan et al observed HLA-I upregulation in breast cancer cell lines following topotecan treatment due to elevated levels of IFN-β signaling.…”

Section: Microenvironmental Regulation Of Hla Expressionmentioning

confidence: 99%

Deregulation of HLA-I in cancer and its central importance for immunotherapy

Hazini

Fisher

Seymour

2021

J Immunother Cancer

115

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It is now well accepted that many tumors undergo a process of clonal selection which means that tumor antigens arising at various stages of tumor progression are likely to be represented in just a subset of tumor cells. This process is thought to be driven by constant immunosurveillance which applies selective pressure by eliminating tumor cells expressing antigens that are recognized by T cells. It is becoming increasingly clear that the same selective pressure may also select for tumor cells that evade immune detection by acquiring deficiencies in their human leucocyte antigen (HLA) presentation pathways, allowing important tumor antigens to persist within cells undetected by the immune system. Deficiencies in antigen presentation pathway can arise by a variety of mechanisms, including genetic and epigenetic changes, and functional antigen presentation is a hard phenomenon to assess using our standard analytical techniques. Nevertheless, it is likely to have profound clinical significance and could well define whether an individual patient will respond to a particular type of therapy or not. In this review we consider the mechanisms by which HLA function may be lost in clinical disease, we assess the implications for current immunotherapy approaches using checkpoint inhibitors and examine the prognostic impact of HLA loss demonstrated in clinical trials so far. Finally, we propose strategies that might be explored for possible patient stratification.

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Section: Microenvironmental Regulation Of Hla Expressionmentioning

confidence: 99%

Deregulation of HLA-I in cancer and its central importance for immunotherapy

Hazini

Fisher

Seymour

2021

J Immunother Cancer

115

View full text Add to dashboard Cite

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“…IFN1 biological activity is mediated by a heterodimeric receptor complex composed of IFNAR1 and IFNAR2 chains [ 83 ]. Proteolytic loss of IFNAR1 in the nonimmune tumor microenvironment promotes a stable activation of CAFs and enhances tumor growth, whereas stabilization of the receptor attenuates the pro-tumorigenic phenotype of CAFs [ 84 ]. Mice deficient in IFNAR1 exhibit enhanced expression of Smad7 in fibroblasts, and knockdown of Smad7 in such cells alleviates deficient ECM production in response to TGF-β1 [ 84 ].…”

Section: Smad7 In Colon Cancermentioning

confidence: 99%

“…Proteolytic loss of IFNAR1 in the nonimmune tumor microenvironment promotes a stable activation of CAFs and enhances tumor growth, whereas stabilization of the receptor attenuates the pro-tumorigenic phenotype of CAFs [ 84 ]. Mice deficient in IFNAR1 exhibit enhanced expression of Smad7 in fibroblasts, and knockdown of Smad7 in such cells alleviates deficient ECM production in response to TGF-β1 [ 84 ]. These data raise the possibility that Smad7 is one of the mediators of the IFN1-driven suppression of stromagenesis.…”

Section: Smad7 In Colon Cancermentioning

confidence: 99%

Involvement of Smad7 in Inflammatory Diseases of the Gut and Colon Cancer

Troncone

Marafini

Stolfi

et al. 2021

IJMS

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In physiological conditions, the human intestinal mucosa is massively infiltrated with various subsets of immune cells, the activity of which is tightly regulated by several counter-regulatory factors. One of these factors is transforming growth factor-β1 (TGF-β1), a cytokine produced by multiple cell types and targeting virtually all the intestinal mucosal cells. Binding of TGF-β1 to its receptors triggers Smad2/3 signaling, thus culminating in the attenuation/suppression of immune–inflammatory responses. In patients with Crohn’s disease and patients with ulcerative colitis, the major human inflammatory bowel diseases (IBD), and in mice with IBD-like colitis, there is defective TGF-β1/Smad signaling due to high levels of the intracellular inhibitor Smad7. Pharmacological inhibition of Smad7 restores TGF-β1 function, thereby reducing inflammatory pathways in patients with IBD and colitic mice. On the other hand, transgenic over-expression of Smad7 in T cells exacerbates colitis in various mouse models of IBD. Smad7 is also over-expressed in other inflammatory disorders of the gut, such as refractory celiac disease, necrotizing enterocolitis and cytomegalovirus-induced colitis, even though evidence is still scarce and mainly descriptive. Furthermore, Smad7 has been involved in colon carcinogenesis through complex and heterogeneous mechanisms, and Smad7 polymorphisms could influence cancer prognosis. In this article, we review the data about the expression and role of Smad7 in intestinal inflammation and cancer.

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“…Our findings showed that Sac/Val markedly suppressed the activation of the TGF-β1/Smad3 signaling pathway during the progression of the high-salt diet-induced cardiac fibrosis. The expression of Smad7, which is a feedback inhibitor of TGF-β, was increased by treatment with Sac/Val ( Cho et al, 2020 ), suggesting that this pathway was probably involved in the cardioprotective effects of Sac/Val.…”

Section: Discussionmentioning

confidence: 99%

Sacubitril/Valsartan Reduces Fibrosis and Alleviates High-Salt Diet-Induced HFpEF in Rats

Zhang

Liu

et al. 2021

Front. Pharmacol.

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Previous studies have confirmed the clinical efficacy of sacubitril/valsartan (Sac/Val) for the treatment of heart failure with reduced ejection fraction (HFrEF). However, the role of Sac/Val in heart failure with preserved ejection fraction (HFpEF) remains unclear. Sac/Val is a combination therapeutic medicine comprising sacubitril and valsartan that acts as a first angiotensin receptor blocker and neprilysin inhibitor (angiotensin-receptor neprilysin inhibitor (ARNI)). Here, we investigated the role of Sac/Val in high-salt diet-induced HFpEF coupled with vascular injury as well as the underlying mechanism. Rats were fed with high-salt feed, followed by intragastric administration of Sac/Val (68 mg/kg; i.g.). The results of functional tests revealed that a high-salt diet caused pathological injuries in the heart and vascular endothelium, which were significantly reversed by treatment with Sac/Val. Moreover, Sac/Val significantly decreased the levels of fibrotic factors, including type I collagen and type Ⅲ collagen, thus, reducing the ratio of MMP2/TIMP2 while increasing Smad7 levels. Further investigation suggested that Sac/Val probably reversed the effects of high-salt diet-induced HFpEF by inhibiting the activation of the TGF-β1/Smad3 signaling pathway. Thus, treatment with Sac/Val effectively alleviated the symptoms of high-salt diet-induced HFpEF, probably by inhibiting fibrosis via the TGF-β1/Smad3 signaling pathway, supporting the therapeutic potential of Sac/Val for the treatment of HFpEF.

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Cancer-associated fibroblasts downregulate type I interferon receptor to stimulate intratumoral stromagenesis

Cited by 19 publications

References 39 publications

Deregulation of HLA-I in cancer and its central importance for immunotherapy

Deregulation of HLA-I in cancer and its central importance for immunotherapy

Involvement of Smad7 in Inflammatory Diseases of the Gut and Colon Cancer

Sacubitril/Valsartan Reduces Fibrosis and Alleviates High-Salt Diet-Induced HFpEF in Rats

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