Extracellular vesicle-mediated transfer of functional RNA in the tumor microenvironment

Ridder, Kirsten De; Sevko, Alexandra; Heide, Janina; Dams, Maria; Rupp, Anne-Kathleen; Macas, Jadranka; Starmann, Julia; Tjwa, Marc; Plate, Karl H.; Sültmann, Holger; Altevogt, Peter; Umansky, Viktor; Momma, Stefan

doi:10.1080/2162402x.2015.1008371

Cited by 242 publications

(262 citation statements)

References 33 publications

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“…Loss of CD16 expression has been reported on NK cells recovered from ovarian patient ascites and was connected to loss of cytotoxic function. 33,34 Interestingly, NK cells from animals treated with anti-PD-L1 also had greater frequencies of CD57 + NK cells (30 vs . 47%, p = 0.0014; Figure 4C) which have been correlated with memory-like phenotype and are associated in several studies with better outcomes and improved long-term survival across many tumor types.…”

Section: Resultsmentioning

confidence: 99%

PD-L1 blockade enhances anti-tumor efficacy of NK cells

2018

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Anti-PD-1/anti-PD-L1 therapies have shown success in cancer treatment but responses are limited to ~ 15% of patients with lymphocyte infiltrated, PD-L1 positive tumors. Hence, strategies that increase PD-L1 expression and tumor infiltration should make more patients eligible for PD-1/PD-L1 blockade therapy, thus improving overall outcomes. PD-L1 expression on tumors is induced by IFNγ, a cytokine secreted by NK cells. Therefore, we tested if PM21-particle expanded NK cells (PM21-NK cells) induced expression of PD-L1 on tumors and if anti-PD-L1 treatment enhanced NK cell anti-tumor efficacy in an ovarian cancer model. Studies here showed that PM21-NK cells secrete high amounts of IFNγ and that adoptively transferred PM21-NK cells induce PD-L1 expression on SKOV-3 cells in vivo. The induction of PD-L1 expression on SKOV-3 cells coincided with the presence of regulatory T cells (Tregs) in the abdominal cavity and within tumors. In in vitro experiments, anti-PD-L1 treatment had no direct effect on cytotoxicity or cytokine secretion by predominantly PD-1 negative PM21-NK cells in response to PD-L1+ targets. However, significant improvement of NK cell anti-tumor efficacy was observed in vivo when combined with anti-PD-L1. PD-L1 blockade also resulted in increased in vivo NK cell persistence and retention of their cytotoxic phenotype. These results support the use of anti-PD-L1 in combination with NK cell therapy regardless of initial tumor PD-L1 status and indicate that NK cell therapy would likely augment the applicability of anti-PD-L1 treatment.

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Section: Resultsmentioning

confidence: 99%

PD-L1 blockade enhances anti-tumor efficacy of NK cells

2018

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“…PD-L2 IHC was performed as described. 39 Immunoreactions were visualized using streptavidin-biotin-peroxidase (Dako Agilent Technologies, E0432, E0433, P0397) and the DAB Chromogen System (Dako Agilent Technologies, K3468) followed by counterstaining with Carazzi hematoxylin. Positive tumors contained cell cytoplasmic chemokine staining in at least 10% of tumor or stromal cells, as described.…”

Section: Methodsmentioning

confidence: 99%

HER2 signaling regulates the tumor immune microenvironment and trastuzumab efficacy

et al. 2018

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Through whole-transcriptome profiling of HER2+ breast carcinomas (BCs), we previously showed that those sensitive to trastuzumab are addicted to this oncoprotein and are enriched in immune pathways, raising the hypothesis that HER2 itself regulates immune cell recruitment. In the present study we investigated the relationship between HER2 activity and the pro-trastuzumab tumor immune milieu. Gene expression profiling and immunohistochemistry analysis of 53 HER2+ BCs showed that trastuzumab-sensitive tumors expressed significantly higher levels of chemokines involved in immune cell recruitment, with higher infiltration of T cells and monocytes, and higher levels of PD-1 ligands than tumors that do not benefit from trastuzumab. In vitro analysis in HER2+ BC cells revealed that CCL2 production was induced by HER2 stimulation with EGF/HRG via the PI3K-NF-kB axis, and down-modulated by HER2 inhibition with trastuzumab. CCL2 expression was higher in HER2+/ER− than HER2+/ER+ BC cell lines, and degradation of ER by fulvestrant induced an enhancement in NF-κB transcriptional activity and consequent CCL2 expression. Trastuzumab efficacy relied on CCL2 levels and monocytes present in the tumor microenvironment in FVB mice bearing HER2+ mammary carcinoma cells. HER2 signals were also found to sustain the expression of PD-1 ligands in tumor cells via the MEK pathway.Overall, our results support the concept that the activated HER2 oncogene regulates recruitment and activation of tumor infiltrating immune cells and trastuzumab activity by inducing CCL2 and PD-1 ligands and that ER activity negatively controls the HER2-driven pro-trastuzumab tumor microenvironment.

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“…Another effective and more proven method utilizes the Cre–LoxP system, in which transgenic mice express the LacZ reporter gene with a STOP sequence, which can be excised by Cre to subsequently exhibit LacZ expression after transfection with EVs containing Cre mRNA 113. This method has been successfully used several times 117, 118…”

Section: Modular Design Of Internal Contentsmentioning

confidence: 99%

Modularized Extracellular Vesicles: The Dawn of Prospective Personalized and Precision Medicine

2018

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Extracellular vesicles (EVs) are ubiquitous nanosized membrane vesicles consisting of a lipid bilayer enclosing proteins and nucleic acids, which are active in intercellular communications. EVs are increasingly seen as a vital component of many biological functions that were once considered to require the direct participation of stem cells. Consequently, transplantation of EVs is gradually becoming considered an alternative to stem cell transplantation due to their significant advantages, including their relatively low probability of neoplastic transformation and abnormal differentiation. However, as research has progressed, it is realized that EVs derived from native‐source cells may have various shortcomings, which can be corrected by modification and optimization. To date, attempts are made to modify or improve almost all the components of EVs, including the lipid bilayer, proteins, and nucleic acids, launching a new era of modularized EV therapy through the “modular design” of EV components. One high‐yield technique, generating EV mimetic nanovesicles, will help to make industrial production of modularized EVs a reality. These modularized EVs have highly customized “modular design” components related to biological function and targeted delivery and are proposed as a promising approach to achieve personalized and precision medicine.

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Extracellular vesicle-mediated transfer of functional RNA in the tumor microenvironment

Abstract: (2015) Extracellular vesicle-mediated transfer of functional RNA in the tumor microenvironment, OncoImmunology, 4:6, e1008371,

Cited by 242 publications

References 33 publications

PD-L1 blockade enhances anti-tumor efficacy of NK cells

PD-L1 blockade enhances anti-tumor efficacy of NK cells

HER2 signaling regulates the tumor immune microenvironment and trastuzumab efficacy

Modularized Extracellular Vesicles: The Dawn of Prospective Personalized and Precision Medicine

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