Epithelial-mesenchymal transition leads to NK cell–mediated metastasis-specific immunosurveillance in lung cancer

Chockley, Peter; Chen, Jun; Chen, Guoan; Beer, David G.; Standiford, Theodore J.; Keshamouni, Venkateshwar G.

doi:10.1172/jci97611

Cited by 115 publications

(105 citation statements)

References 57 publications

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“…Interestingly, a recent study indicates that after an epithelial-mesenchymal transition, tumor cells are particularly sensitive to NK cell killing, again suggesting that tumor cells are not equal in term of immunosurveillance (17). Based on our results, we propose that these cancer cell subsets with mesenchymal features, located at the periphery of tumor islets are more prone to stimulate CAR T cells through the expression of one or several proteins that remain to be identified…”

Section: Discussionsupporting

confidence: 64%

CAR T cell entry into tumor islets is a two-step process dependent on IFNγ and ICAM-1

Kantari‐Mimoun

Barrin

Haghiri

et al. 2020

Preprint

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Adoptive transfer of T cells expressing chimeric antigen receptors (CARs) has shown remarkable clinical efficacy against advanced B cell malignancies but not yet against solid tumors. Here, we used fluorescent imaging microscopy and ex vivo assays to compare the early functional responses (migration, Ca2+ and cytotoxicity) of CD20 and EGFR CAR T cells upon contact with malignant B and carcinoma cells. Our results indicate that CD20 CAR T cells rapidly form productive ICAM-1-dependent conjugates with their targets. By comparison, EGFR CAR T cells only interact at first with a subset of carcinoma cells located at the periphery of tumor islets. After this initial peripheral activation, EGFR CAR T cells progressively infiltrate the center of tumor cell regions. The analysis of this two-step entry process shows that activated CAR T cells trigger the upregulation of ICAM-1 on tumor cells in an IFNγ-dependent pathway. The blockade of ICAM-1/LFA-1 interactions prevents CAR T cell recruitment into tumor islets. The requirement for IFNγ and ICAM-1 to enable CAR T cell entry into tumor islets is of significance for improving CAR T strategy in solid tumors.

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Section: Discussionsupporting

confidence: 64%

CAR T cell entry into tumor islets is a two-step process dependent on IFNγ and ICAM-1

Kantari‐Mimoun

Barrin

Haghiri

et al. 2020

Preprint

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“…Thus, for example, EMT has been shown to induce an immunosuppressive microenvironment in hepatocellular carcinoma (40), or to reduce the ability of breast cancer cells to form immunologic synapses with cytotoxic T lymphocytes (34). On the other hand, it has also been reported that EMT induction could promote NKG2D-L upregulation on colorectal cells and on immortalized keratinocytes, or induce increased NK cell-mediated metastasis-specific immunosurveillance in lung cancer (41,42). Nevertheless, besides HLA-I molecules, no major NK-receptor ligands were significantly modified by EMT in our experiments on melanoma cells ( Supplementary Fig.…”

Section: Discussionmentioning

confidence: 99%

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

et al. 2018

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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. .

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“…A study by Huergo-Zapico et al recently showed that NK-cells could mediate EMT programs in melanoma cells, simultaneously potentiating the immune resistance capacity of the latter. On the contrary, data from at least two studies using various model systems have raised the possibility that EMT induction could increase cancer cell susceptibility to NK cells through up-regulation of NKG2D ligands or cell adhesion molecule 1 (CADM1) [ 59 , 60 ]. This further highlights the contextual nature of the events.…”

Section: Impact Of Plasticity and Heterogeneity On Tumor Immune Esmentioning

confidence: 99%

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

Terry

Zaarour

Venkatesh

et al. 2018

IJMS

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Hypoxia, or gradients of hypoxia, occurs in most growing solid tumors and may result in pleotropic effects contributing significantly to tumor aggressiveness and therapy resistance. Indeed, the generated hypoxic stress has a strong impact on tumor cell biology. For example, it may contribute to increasing tumor heterogeneity, help cells gain new functional properties and/or select certain cell subpopulations, facilitating the emergence of therapeutic resistant cancer clones, including cancer stem cells coincident with tumor relapse and progression. It controls tumor immunogenicity, immune plasticity, and promotes the differentiation and expansion of immune-suppressive stromal cells. In this context, manipulation of the hypoxic microenvironment may be considered for preventing or reverting the malignant transformation. Here, we review the current knowledge on how hypoxic stress in tumor microenvironments impacts on tumor heterogeneity, plasticity and resistance, with a special interest in the impact on immune resistance and tumor immunogenicity.

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Epithelial-mesenchymal transition leads to NK cell–mediated metastasis-specific immunosurveillance in lung cancer

Abstract: .(S4945; Sigma-Aldrich) with subsequent anti-rabbit-Alexa Fluor 488 (R37116) secondary antibody.

Cited by 115 publications

References 57 publications

CAR T cell entry into tumor islets is a two-step process dependent on IFNγ and ICAM-1

CAR T cell entry into tumor islets is a two-step process dependent on IFNγ and ICAM-1

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

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

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