NK-cell Editing Mediates Epithelial-to-Mesenchymal Transition via Phenotypic and Proteomic Changes in Melanoma Cell Lines

Abstract

Tumor cell plasticity is a major obstacle for the cure of malignancies as it makes tumor cells highly adaptable to microenvironmental changes, enables their phenotype switching among different forms, and favors the generation of prometastatic tumor cell subsets. Phenotype switching toward more aggressive forms involves different functional, phenotypic, and morphologic changes, which are often related to the process known as epithelial-mesenchymal transition (EMT). In this study, we report natural killer (NK) cells may increase the malignancy of melanoma cells by inducing changes relevant to EMT and, more broadly, to phenotype switching from proliferative to invasive forms. In coculture, NK cells induced effects on tumor cells similar to those induced by EMT-promoting cytokines, including upregulation of stemness and EMT markers, morphologic transition, inhibition of proliferation, and increased capacity for Matrigel invasion. Most changes were dependent on the engagement of NKp30 or NKG2D and the release of cytokines including IFNγ and TNFα. Moreover, EMT induction also favored escape from NK-cell attack. Melanoma cells undergoing EMT either increased NK-protective HLA-I expression on their surface or downregulated several tumor-recognizing activating receptors on NK cells. Mass spectrometry-based proteomic analysis revealed in two different melanoma cell lines a partial overlap between proteomic profiles induced by NK cells or by EMT cytokines, indicating that various processes or pathways related to tumor progression are induced by exposure to NK cells. NK cells can induce prometastatic properties on melanoma cells that escape from killing, providing important clues to improve the efficacy of NK cells in innovative antitumor therapies. .

Role of Hypoxic Stress in Regulating Tumor Immunogenicity, Resistance and Plasticity

“…Ricciardi and colleagues observed that exposing carcinoma cells to inflammatory cytokines not only promotes EMT in these cells but also confers a number of immunomodulatory properties, including interference with proliferation, differentiation and apoptosis of NK, T and B cell populations [ 55 ]. On the other hand, immune cells such as macrophages and NK cells can also mediate EMT of cancer cells, and presumably, could influence immune resistant states of carcinoma cells [ 56 , 57 , 58 ].…”

Cell stemness, epithelial-to-mesenchymal transition, and immunoevasion: Intertwined aspects in cancer metastasis

“…The suppression mechanism of immune cells was partly mediated by activating the IDO pathway [51]. Alternatively, NK cells can positively influence EMT, as shown by Huergo-Zapigo et al [52]. Those authors found that NK cells produced proteomic changes in melanoma cells that largely overlapped with those of cytokine-induced EMT.…”

Immune system and bone microenvironment: rationale for targeted cancer therapies

“…On the other hand, several data showed that NK cells promote melanoma cells proliferation and CSC phenotype conversion into bone niche. Furthermore, B and T cells contribute to the process of osteoclastogenesis, by the production of different factors such as TNFα and RANKL [26].…”