Suppression of natural killer cell activity by adherent effusion cells of cancer patients. Suppression of motility, binding capacity and lethal hit of NK cells

Uchida, Atsushi; Colot, M.; Micksche, M.

doi:10.1038/bjc.1984.4

Cited by 20 publications

(5 citation statements)

References 20 publications

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“…Notably, upregulation of PDL1 on tumor cells required NK cells capable of potent activation in response to tumors, as treatment of tumors with freshly isolated pbNK cells, known to be suppressed by tumors, had no effect on tumor PDL1 ( figure 2E ). 14 These findings identify that exNK cells could be harnessed to increase the proportion of patients who are likely to benefit from PD1-blockade therapy.…”

Section: Resultsmentioning

confidence: 97%

Expanded human NK cells from lung cancer patients sensitize patients’ PDL1−negative tumors to PD1-blockade therapy

Poznanski

Ritchie

Fan

et al. 2021

J Immunother Cancer

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Lung cancer remains the leading cause of cancer death worldwide despite the significant progress made by immune checkpoint inhibitors, including programmed death receptor-1 (PD1)/PD ligand 1 (PDL1)-blockade therapy. PD1/PDL1−blockade has achieved unprecedented tumor regression in some patients with advanced lung cancer. However, the majority of patients fail to respond to PD1/PDL1 inhibitors. The high rate of therapy non-response results from insufficient PDL1 expression on most patients’ tumors and the presence of further immunosuppressive mechanisms in the tumor microenvironment. Here, we sensitize non-responding tumors from patients with lung cancer to PD1-blockade therapy using highly cytotoxic expanded natural killer (NK) cells. We uncover that NK cells expanded from patients with lung cancer dismantle the immunosuppressive tumor microenvironment by maintaining strong antitumor activity against both PDL1+ and PDL1− patient tumors. In the process, through a contact-independent mechanism involving interferon γ, expanded NK cells rescued tumor killing by exhausted endogenous TILs and upregulated the tumor proportion score of PDL1 across patient tumors. In contrast, unexpanded NK cells, which are susceptible to tumor-induced immunosuppression, had no effect on tumor PDL1. As a result, combined treatment of expanded NK cells and PD1-blockade resulted in robust synergistic tumor destruction of initially non-responding patient tumors. Thus, expanded NK cells may overcome the critical roadblocks to extending the prodigious benefits of PD1-blockade therapy to more patients with lung cancer and other tumor types.

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Section: Resultsmentioning

confidence: 97%

Expanded human NK cells from lung cancer patients sensitize patients’ PDL1−negative tumors to PD1-blockade therapy

Poznanski

Ritchie

Fan

et al. 2021

J Immunother Cancer

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“…However, neither the mechanism of secretion nor the function of secreted vimentin is known. It could be possible that secreted vimentin is bound on the surface of cancer cells and attracts the natural killer cells that harbor the NKp46 receptors to the tumor site, where they get suppressed by different mechanisms (67, 68) thereby creating a tumor immune escape environment that enhances tumor progression. Taken together, these results imply that vimentin transport to cell surface is tightly controlled during development and that several factors, including cytokines can modulate vimentin's extracellular transport.…”

Section: Subcellular Distribution and Export Of Vimentin To Cell Surfacementioning

confidence: 99%

Vimentin in cancer and its potential as a molecular target for cancer therapy

Satelli

2011

Cell. Mol. Life Sci.

1,255

1,052

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Vimentin, a major constituent of the intermediate filament (IF) family of proteins, is ubiquitously expressed in normal mesenchymal cells and is known to maintain cellular integrity and provide resistance against stress. Increased vimentin expression has been reported in various epithelial cancers including prostate cancer, gastrointestinal tumors, CNS tumors, breast cancer, malignant melanoma, lung cancer and other types of cancers. Vimentin's over-expression in cancer correlates well with increased tumor growth, invasion and poor prognosis; however, the role of vimentin in cancer progression remains obscure. In the recent years, vimentin has gained much importance as a marker for epithelial-mesenchymal transition (EMT). Although EMT is associated with a number of tumorigenic events, the role of vimentin in the underlying events mediating these processes remains unknown. Though majority of the literature findings indicate a future significance of vimentin as a biomarker for different cancers with clinical relevance, more research in to the molecular aspects will be crucial to particularly evaluate the function of vimentin in the process of tumorigenesis. By virtue of its over-expression in a large number of cancers and its role in mediating various tumorigenic events, vimentin serves as an attractive target for cancer therapy. Further, research directed toward elucidating the role of vimentin in various signaling pathways would open up new approaches for the development of promising therapeutic agents. This review summarizes the expression and functions of vimentin in cancers and also suggests some directions toward future cancer therapy utilizing vimentin as a potential target.

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“…However, once the lung tumours are established, another situation might arise comprising a direct inhibition of nK cell activity by lung cancer cells. thus, it has been shown that lung tumour cells from malignant pleural effusions inhibit nK cell activity [39], and it was further demonstrated that nK cells isolated from lung tumours exhibit decreased cytotoxic activity [40].…”

Section: Discussionmentioning

confidence: 99%

Influence of natural killer cells and perforin-mediated cytolysis on the development of chemically induced lung cancer in A/J mice

Frese-Schaper

Keil

Yagita

et al. 2014

Cancer Immunol Immunother

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One alternative approach for the treatment of lung cancer might be the activation of the immune system using vaccination strategies. However, most of clinical vaccination trials for lung cancer did not reach their primary end points, suggesting that lung cancer is of low immunogenicity. To provide additional experimental information about this important issue, we investigated which type of immune cells contributes to the protection from lung cancer development. Therefore, A/J mice induced for lung adenomas/ adenocarcinomas by the tobacco-specific nitrosamine 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK) were depleted of CD4+ or CD8+ T cells, CD11b+ macrophages, Gr-1+ neutrophils and asialo GM1+ natural killer (NK) cells. Subsequent analysis of tumour growth showed an increase in tumour number only in mice depleted of NK cells. Further asking by which mechanism NK cells suppressed tumour development, we neutralized several death ligands of the tumour necrosis factor (TNF) family known to be involved in NK cell-mediated cytotoxicity. However neither depletion of TNF-α, TNF-related apoptosis-inducing ligand, TNF-like weak inducer of apoptosis or FasL alone nor in combination induced an augmentation of tumour burden. To show whether an alternative cell death pathway is involved, we next generated A/J mice deficient for perforin. After challenging with NNK, mice deficient for perforin showed an increase in tumour number and volume compared to wild-type A/J mice. In summary, our data suggest that NK cells and perforin-mediated cytolysis are critically involved in the protection from lung cancer giving promise for further immunotherapeutic strategies for this disease.

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Suppression of natural killer cell activity by adherent effusion cells of cancer patients. Suppression of motility, binding capacity and lethal hit of NK cells

Cited by 20 publications

References 20 publications

Expanded human NK cells from lung cancer patients sensitize patients’ PDL1−negative tumors to PD1-blockade therapy

Expanded human NK cells from lung cancer patients sensitize patients’ PDL1−negative tumors to PD1-blockade therapy

Vimentin in cancer and its potential as a molecular target for cancer therapy

Influence of natural killer cells and perforin-mediated cytolysis on the development of chemically induced lung cancer in A/J mice

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