Regulated Polarization of Tumor-Associated Macrophages by miR-145 via Colorectal Cancer–Derived Extracellular Vesicles

Shinohara, Haruka; Kuranaga, Yuki; Kumazaki, Minami; Sugito, Nobuhiko; Yoshikawa, Yuki; Takai, Tomoaki; Taniguchi, Kohei; Ito, Yuko; Akao, Yukihiro

doi:10.4049/jimmunol.1700167

Cited by 138 publications

(101 citation statements)

References 38 publications

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“…Concurrent protein expression was observed for IL‐10 and IL‐12p40 in the culture media of these cells. Furthermore, this effect was confirmed to be tEV‐mediated by replication of the above results with direct application of isolated tEVs . The observed effects were attributed, at least in part, to miR‐145 which was enriched in tEVs compared to parent cells.…”

Section: Immunomodulatory Role Of Crc‐derived Evssupporting

confidence: 61%

“…In the first, Shinohara et al . (2016) used THP‐1 cells differentiated with 12‐O‐tetradecanoylphorbol13‐acetate for 24 h to create macrophage‐like cells prior to co‐culture with the CRC cell line DLD‐1 . M2 phenotype switch was indicated by increased CD11b + CD68 + CD206 + cell populations and upregulated IL‐10 and VEGFA mRNA (M2 associated cytokines) with downregulated IL‐12p40 and TNF‐α mRNA (M1 associated cytokines).…”

Section: Immunomodulatory Role Of Crc‐derived Evsmentioning

confidence: 99%

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The immunomodulatory role of tumor‐derived extracellular vesicles in colorectal cancer

Manning

Danielson

2018

Immunol Cell Biol

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Colorectal cancer (CRC) is one of the most prevalent cancers worldwide with rising mortality rates predicted in the coming decades. In light of this, there is a continued need for improvement in our understanding of CRC biology and the development of novel treatment options. Tumor-derived extracellular vesicles (tEVs) have emerged as both novel cancer biomarkers and functional mediators of carcinogenesis. tEVs are released by tumor cells in abundance and play an important role in mediating tumor cell-immune cell interactions in the tumor microenvironment. Furthermore, tEVs are released into the circulation in humans where they could also interact with circulating immune cells. This review aims to describe CRC-specific tEVs and what is currently known about their role in immunomodulation. In particular, we discuss the ability of CRC-derived tEVs to affect monocyte differentiation into macrophages and dendritic cells, and their effects on T-cell viability and activity. Finally, the potential for tEVs in the development of immunotherapies will be discussed.

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Section: Immunomodulatory Role Of Crc‐derived Evssupporting

confidence: 61%

Section: Immunomodulatory Role Of Crc‐derived Evsmentioning

confidence: 99%

The immunomodulatory role of tumor‐derived extracellular vesicles in colorectal cancer

Manning

Danielson

2018

Immunol Cell Biol

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“…Currently, it is unclear how the tumor microenvironment achieves this massive influx of monocytes and macrophages and how it initiates genetic reprogramming of TAMs. While tumor-derived miRs that alter the macrophage phenotype have been reported in this review and elsewhere [123], our study provides evidence that miR-375 provokes monocyte/macrophage migration and infiltration without affecting cell polarization [38]. To identify miR-375 targets in macrophages, we overexpressed miR-375 using a synthetic miR-mimic and subsequently performed AGO-RIP-Seq.…”

Section: Guo Et Al Investigated Mechanisms Of Breast Cancer Invasionmentioning

confidence: 72%

“…In macrophages, miR-1246 triggers anti-inflammatory immunosuppression, with an increased activity of transforming growth factor β (TGFβ) [122]. Moreover, colorectal cancer EVs containing miR-145 polarize macrophages to the M2 phenotype through downregulation of histone deacetylase 11 (HDAC11) [123].…”

Section: Colon Cancermentioning

confidence: 99%

MicroRNA—A Tumor Trojan Horse for Tumor-Associated Macrophages

Syed

Frank

Raue

et al. 2019

Cells

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MicroRNAs (miRs) significantly contribute to the regulation of gene expression, by virtue of their ability to interact with a broad, yet specific set of target genes. MiRs are produced and released by almost every cell type and play an important role in horizontal gene regulation in the tumor microenvironment (TME). In the TME, both tumor and stroma cells cross-communicate via diverse factors including miRs, which are taking central stage as a therapeutic target of anti-tumor therapy. One of the immune escape strategies adopted by tumor cells is to release miRs as a Trojan horse to hijack circulating or tumor-localized monocytes/macrophages to tune them for pro-tumoral functions. On the other hand, macrophage-derived miRs exert anti-tumor functions. The transfer of miRs from host to recipient cells depends on the supramolecular structure and composition of miR carriers, which determine the distinct uptake mechanism by recipient cells. In this review, we provide a recent update on the miR-mediated crosstalk between tumor cells and macrophages and their mode of uptake in the TME.(TNF-α), and provoke the secretion of pro-inflammatory cytokines including interleukin-1 (IL-1), IL-6, IL-12, IL-23, and TNF-α and reactive nitrogen and oxygen intermediates (RNI, ROI) [5]. In contrast, anti-inflammatory stimuli such as IL-4, IL-13, IL-10, and glucocorticoid or immune complexes (IC) plus LPS induce macrophages to an M2 phenotype. This type is characterized by a decreased production of pro-inflammatory cytokines, increased production of anti-inflammatory cytokines (e.g., IL-10), and factors that mediate immunosuppression and tissue remodeling. M2 macrophages have been divided into further subgroups. The M2a type is generated in response to IL-3 and IL-13, while M2b macrophages respond to immune complexes and Toll-like receptor (TLR) activation. M2c macrophages represent deactivated macrophages that suppress pro-inflammatory cytokines, while the M2d type represents a regulatory macrophage [6] that is often grouped with TAMs [5,7,8]. In line with these varied responses, Janus-faced macrophage functions are largely determined by their microenvironment rather than their genetic imprint [9,10]. In tumors and during the resolution of inflammation, hijacked macrophages attain pro-tumor or wound healing phenotypes due to tumor-derived factors [11], which emerge as a target for tumor therapy [12,13]. TAMs expressing classical activation markers produce pro-inflammatory cytokines and reactive oxygen species (ROS) and, thus, are crucial for tumor cell killing [14,15]. The high degree of plasticity demonstrated by macrophages in pathological conditions can be attributed to a) dynamic regulation of gene expression and b) rapid activation of signaling cascades that determine their effector functions. Signaling cascades triggered by local environmental cues and controlling the transcriptional machinery, ultimately determine the effector functions of macrophages in the tumor microenvironment (TME). Hence, understanding and modulating these ...

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“…More specifically it has been proposed that mutant TP53 colon cancer cells reprogram macrophages to tumor supporting macrophages via miR-1246 delivered by EVs (Cooks et al, 2018). Colorectal cancer−derived EVs were described to regulate polarization of tumor-associated macrophages by the miR-145 which is transcriptionally induced by p53 (Sachdeva et al, 2009;Shinohara et al, 2017). As for the context of chemotherapy and DNA damage, EV-based metabolic reprogramming by tissue-infiltrating macrophages underlines the role of EVs in cellular crosstalk (Goulielmaki et al, 2020).…”

Section: Discussionmentioning

confidence: 99%

Loss of TP53 mediates suppression of Macrophage Effector Function via Extracellular Vesicles and PDL1 towards Resistance against Chemoimmunotherapy in B-cell malignancies

Izquierdo

Vorholt

Sackey

et al. 2020

Preprint

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Highlights• Loss of TP53 in B-cell lymphoma induces resistance towards chemoimmunotherapy (CIT) by inhibition of macrophage effector function through PDL1 upregulation • Loss of TP53 increases formation of extracellular vesicles (EVs) carrying PDL1 • EVs inhibit antibody-mediated cellular phagocytosis (ADCP), a key macrophage effector function in CIT • Targeting PDL1 on EVs with immune checkpoint inhibitors overcomes TP53-mediated resistance to CIT Summary Chemoimmunotherapy (CIT) is the standard of care in B-cell malignancies. It is relying on synergistic effects of alkylating chemotherapy and monoclonal antibodies via secretory crosstalk with effector macrophages. Here, we observed that loss of p53 function mediates resistance to CIT by suppressing macrophage phagocytic function. Loss of p53 leads to an upregulation of PDL1 and an increased formation of extracellular vesicles (EVs). EVs directly inhibit macrophage phagocytosis by PDL1 surface expression. Suppression of phagocytic function by lymphoma cell-derived EVs could be abrogated by pre-incubation of EVs with anti-PDL1 antibodies, CRISPR-KO of PDL1 and abrogation of EV formation by RAB27A-KO in lymphoma cells. Immune checkpoint inhibition represents a viable 3 strategy to overcome EV-mediated resistance to chemoimmunotherapy in lymphoma. SignificanceLoss of TP53 mediates cell autonomous resistance to genotoxic chemotherapy, moreover non-cell autonomous effects may cause therapy resistance mediated by the tumor microenvironment. We identify a TP53dependent mechanism that mediates resistance to synergistic chemoimmunotherapy by increasing formation of EVs and expression of the PDL1 immune checkpoint. PDL1 on EVs is directly responsible for macrophage suppression, preventing the exertion of the essential effector function of antibody-dependent cellular phagocytosis. This novel mechanism of resistance is in turn targetable by PDL1 checkpoint inhibition. Enhanced EV-release and immune checkpoint expression in lymphoma are novel mechanisms of macrophage modulation in the lymphoma microenvironment.We provide a novel principle of resistance to chemoimmunotherapy (CIT) representing of immediate relevance to treatment of refractory B-cell lymphoma.

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Regulated Polarization of Tumor-Associated Macrophages by miR-145 via Colorectal Cancer–Derived Extracellular Vesicles

Cited by 138 publications

References 38 publications

The immunomodulatory role of tumor‐derived extracellular vesicles in colorectal cancer

The immunomodulatory role of tumor‐derived extracellular vesicles in colorectal cancer

MicroRNA—A Tumor Trojan Horse for Tumor-Associated Macrophages

Loss of TP53 mediates suppression of Macrophage Effector Function via Extracellular Vesicles and PDL1 towards Resistance against Chemoimmunotherapy in B-cell malignancies

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