TGFβ activating integrins β6 and β8 are dysregulated in inflammatory skin disease and cutaneous melanoma

Nguyen, Breanna A.; Ho, Jonhan; Diaz, Jacinto S. De La Cruz; Nishimura, Stephen L.; Kaplan, Daniel H.

doi:10.1016/j.jdermsci.2022.01.008

Cited by 6 publications

(5 citation statements)

References 24 publications

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“…Our current experiments do not determine whether LCs are ignorant of melanoma growth or retained in the skin at early time points. We observed a trend in increase in TGF-β production by some YUMM tumors at day 14, and it has recently been shown that expression of the TGFβ-activating integrin αvβ8 in patients correlates with Breslow depth (71). Thus, activation of LC autocrine latent TGF-β by melanoma αvβ8 may contribute to retention of LCs in the skin.…”

Section: Discussionsupporting

confidence: 58%

Localized immune surveillance of primary melanoma in the skin deciphered through executable modeling

et al. 2023

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While skin is a site of active immune surveillance, primary melanomas often escape detection. Here, we have developed an in silico model to determine the local cross-talk between melanomas and Langerhans cells (LCs), the primary antigen-presenting cells at the site of melanoma development. The model predicts that melanomas fail to activate LC migration to lymph nodes until tumors reach a critical size, which is determined by a positive TNF-α feedback loop within melanomas, in line with our observations of murine tumors. In silico drug screening, supported by subsequent experimental testing, shows that treatment of primary tumors with MAPK pathway inhibitors may further prevent LC migration. In addition, our in silico model predicts treatment combinations that bypass LC dysfunction. In conclusion, our combined approach of in silico and in vivo studies suggests a molecular mechanism that explains how early melanomas develop under the radar of immune surveillance by LC.

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Section: Discussionsupporting

confidence: 58%

Localized immune surveillance of primary melanoma in the skin deciphered through executable modeling

et al. 2023

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“…In another recent study, it was shown that TGFβ is important in maintaining functional LCs and memory T cells in the skin. Moreover, authors show that integrins avβ6 and avβ8, which are able to activate latent TGFβ, were increased in human keratinocytes from psoriatic skin, which might contribute to maintaining cutaneous inflammation [32]. We have shown increased numbers of epidermal LCs with predominant basal/suprabasal, as well as dermal location, in psoriatic skin lesions (Figure 2).…”

Section: Role Of Langerhans Cells In Psoriasismentioning

confidence: 75%

“…We have shown increased numbers of epidermal LCs with predominant basal/suprabasal, as well as dermal location, in psoriatic skin lesions (Figure 2). keratinocytes from psoriatic skin, which might contribute to maintaining cutaneous inflammation [32]. We have shown increased numbers of epidermal LCs with predominant basal/suprabasal, as well as dermal location, in psoriatic skin lesions (Figure 2).…”

Section: Role Of Langerhans Cells In Psoriasismentioning

confidence: 82%

“…Mechanistically, it seems that TGFβ, produced by keratinocytes overexpressing avβ6 and avβ8, retains CD8 + resident memory T cells and LCs in the epidermis [71]. Recently, it was postulated that high levels of avβ8 create a TGFβ-rich TME, thus promoting the accumulation of non-tumor antigen specific T cells and preventing effective anti-tumor immunity [32].…”

Section: Skin Cancersmentioning

confidence: 99%

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Langerhans Cells—Revising Their Role in Skin Pathologies

Neagu

Constantin

Jugulete

et al. 2022

JPM

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Langerhans cells (LCs) constitute a cellular immune network across the epidermis. Because they are located at the skin barrier, they are considered immune sentinels of the skin. These antigen-presenting cells are capable of migrating to skin draining lymph nodes to prime adaptive immune cells, namely T- and B-lymphocytes, which will ultimately lead to a broad range of immune responses. Moreover, LCs have been shown to possess important roles in the anti-cancer immune responses. Indeed, the literature nicely highlights the role of LCs in melanoma. In line with this, LCs have been found in melanoma tissues where they contribute to the local immune response. Moreover, the immunogenic properties of LCs render them attractive targets for designing vaccines to treat melanoma and autoimmune diseases. Overall, future studies will help to enlarge the portfolio of immune properties of LCs, and aid the prognosis and development of novel therapeutic approaches to treating skin pathologies, including cancers.

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“…A mechanism of resistance to glioblastoma treatment with temozolomide was also uncovered with a modulation of integrin α5β1 [ 27 ]. Among others, integrins β3, β6, α2, and β1 are some of the subunits suggested to identify specific cancers such as melanoma, non-small-cell lung cancer and carcinomas, albeit most research is directed to in vivo, in vitro, or in silico approaches [ 28 , 29 , 30 , 31 ].…”

Section: Integrins In Tumor Progressionmentioning

confidence: 99%

The Role of αvβ3 Integrin in Cancer Therapy Resistance

Pachane,

Selistre-de-Araujo

2024

Biomedicines

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A relevant challenge for the treatment of patients with neoplasia is the development of resistance to chemo-, immune-, and radiotherapies. Although the causes of therapy resistance are poorly understood, evidence suggests it relies on compensatory mechanisms that cells develop to replace specific intracellular signaling that should be inactive after pharmacological inhibition. One such mechanism involves integrins, membrane receptors that connect cells to the extracellular matrix and have a crucial role in cell migration. The blockage of one specific type of integrin is frequently compensated by the overexpression of another integrin dimer, generally supporting cell adhesion and migration. In particular, integrin αvβ3 is a key receptor involved in tumor resistance to treatments with tyrosine kinase inhibitors, immune checkpoint inhibitors, and radiotherapy; however, the specific inhibition of the αvβ3 integrin is not enough to avoid tumor relapse. Here, we review the role of integrin αvβ3 in tumor resistance to therapy and the mechanisms that have been proposed thus far. Despite our focus on the αvβ3 integrin, it is important to note that other integrins have also been implicated in drug resistance and that the collaborative action between these receptors should not be neglected.

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TGFβ activating integrins β6 and β8 are dysregulated in inflammatory skin disease and cutaneous melanoma

Cited by 6 publications

References 24 publications

Localized immune surveillance of primary melanoma in the skin deciphered through executable modeling

Localized immune surveillance of primary melanoma in the skin deciphered through executable modeling

Langerhans Cells—Revising Their Role in Skin Pathologies

The Role of αvβ3 Integrin in Cancer Therapy Resistance

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