Melanoma-expressed CD70 is involved in invasion and metastasis

Abstract

Background:CD70 is a costimulatory molecule of the tumour necrosis factor family expressed in activated immune cells and some solid tumours. In lymphocytes CD70 triggers T cell-mediated cytotoxicity and mitogen-activated protein kinase phosphorylation.Methods:We evaluated the expression of CD70 in biopsies and melanoma cell lines. Using melanoma cell lines positive or not for CD70, we analysed CD70 function on melanoma progression.Results:We report CD70 expression in human melanoma cell lines and tumour cells from melanoma biopsies. This expression was observed in 95% of primary melanomas but only 37% of metastases. Both monomeric and trimeric forms of CD70 were detected in tumour cell membrane fractions, whereas cytoplasmic fractions contained almost exclusively monomeric CD70. In vitro and in vivo experiments demonstrated that CD70 expression inhibited melanoma cell migration, invasion and pulmonary metastasis implantation independently of the tumour immune microenvironment. Increasing the levels of the trimeric form of CD70 through monoclonal antibody binding led to an increase in CD70+ melanoma cell invasiveness through MAPK pathway activation, RhoE overexpression, ROCK1 and MYPT1 phosphorylation decrease, and stress fibres and focal adhesions disappearance.Conclusions:Our results describe a new non-immunological function of melanoma-expressed CD70, which involves melanoma invasiveness through MAPK pathway, RhoE and cytoskeletal modulation.

Regulatory properties of statins and rho gtpases prenylation inhibitiors to stimulate melanoma immunogenicity and promote anti‐melanoma immune response

“…CD70 is a costimulatory molecule member of the tumor necrosis factor family that is expressed on activated immune cells. We have described that this protein of which tumoral expression is regulated by RhoA GTPases, promote CD70 positive melanoma cells invasiveness by a new non‐immunological mechanism . Altogether our data show that statins and Rho inhibition positively regulate MHC class I and costimulatory molecules expression on melanoma cells.…”

“…Unexpectedly we have demonstrated that GGTases inhibitors down regulate PD‐L1 expression induced by IFN‐γ on melanoma cells improving the ability of Rho inhibition to promote melanoma immunogenicity. Finally we have reported for the first time CD70 expression on human melanoma surface . CD70 is a costimulatory molecule member of the tumor necrosis factor family that is expressed on activated immune cells.…”

Unveiling a CD70-positive subset of cancer-associated fibroblasts marked by pro-migratory activity and thriving regulatory T cell accumulation

“…Although we are the first to describe this effect by CD70-positive CAFs, CD70 overexpression on tumor cells has already been linked with migration in non-small cell lung cancer, melanoma and glioblastoma. [28][29][30] In the latter, knockdown of the CD70 gene resulted in a decrease in genes associated with tumor epithelial-mesenchymal transition (EMT) such as CD44 and SOX2. Also in CRC, overexpression of CD44 has been shown to drive EMT changes.…”

“…Recently, it has been described that CD70 is not only a ligand but contains an underlying signalling cascade whereby activation leads to MAPK activation, RhoE overexpression and cytoskeletal changes, driving migration in melanoma. 29 It has been demonstrated that targeting the CD70/CD27 axis can inhibit an effective anti-tumor immune response by three modes of action: accumulation of Tregs, T-cell apoptosis and skewing T-cell towards T-cell exhaustion. 13 Increased numbers of Tregs have been particularly found in the presence of CD70-expressing tumor cells due the expression of CD27 on the Tregs.…”

Microenvironmental Hypoxia Induces Dynamic Changes in Lung Cancer Synthesis and Secretion of Into Extracellular Vesicles

“…In addition to regulating host immune activation/suppression, CD70 may also play a direct role in metastasis of melanoma cells, where a cytosolic monomeric form of the protein appears to correlate with poor invasion and metastatic capacities. In contrast, increased levels of trimeric CD70 at the outer membrane can activate MAPK/PhoE signalling and may instead enhance melanoma cell invasiveness [54]. In light of the recent report that exosomal PD-L1 can promote immunosuppression and likely inhibit immune checkpoint blockade therapy in melanoma [55], it is possible that CD70/CD27 in EVs may perform similar roles in patients with lung tumours and other types of cancer.…”