Epigenetic therapy reprograms M2-type tumor-associated macrophages into an M1-like phenotype by upregulating miR-7083-5p

Vadevoo, Sri Murugan Poongkavithai; Gunassekaran, Gowri Rangaswamy; Yoo, Jae Do; Kwon, Tae‐Yub; Hur, Keun; Chae, Sehyun; Lee, Byungheon

doi:10.3389/fimmu.2022.976196

Cited by 9 publications

(7 citation statements)

References 41 publications

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“…In addition to antibodies, trabectedin, a chemotherapeutic drug, exerted antitumor growth activity via monocyte and macrophage cytotoxicity 53 . Epigenetic therapies using DNA methylation and histone deacetylation inhibitors skewed M2 macrophages into the M1-like phenotype 54 and stimulated MDSC differentiation into a more-interstitial macrophage-like phenotype 55 , leading to tumor progression and metastasis inhibition. Furthermore, M1-macrophage-derived exosomes engineered to target IL4R and stimulate pro-inflammatory polarization of macrophages skewed M2 macrophages toward M1-like macrophages 56 .…”

Section: Discussionmentioning

confidence: 99%

IL4 receptor targeting enables nab-paclitaxel to enhance reprogramming of M2-type macrophages into M1-like phenotype via ROS-HMGB1-TLR4 axis and inhibition of tumor growth and metastasis

Vadevoo,

Kang,

Gunassekaran

et al. 2024

Theranostics

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Rationale: Nab-paclitaxel (Abx) is widely employed in malignant tumor therapy. In tumor cells and pro-tumoral M2-type macrophages, the IL4 receptor (IL4R) is upregulated. This study aimed to elucidate the selective delivery of Abx to M2-type macrophages by targeting IL4R and reprogramming them into an anti-tumoral M1-type. Methods: Abx was conjugated with the IL4R-binding IL4RPep-1 peptide using click chemistry (IL4R-Abx). Cellular internalization, macrophage reprogramming and signal pathways, and tumor growth and metastasis by IL4R-Abx were examined. Results: IL4R-Abx was internalized into M2 macrophages more efficiently compared to the unmodified Abx and control peptide-conjugated Abx (Ctrl-Abx), which was primarily inhibited using an anti-IL4R antibody and a receptor-mediated endocytosis inhibitor compared with a macropinocytosis inhibitor. IL4R-Abx reprogrammed the M2-type macrophages into M1-like phenotype and increased reactive oxygen species (ROS) levels and extracellular release of high mobility group box 1 (HMGB1) in M2 macrophages at higher levels than Abx and Ctrl-Abx. The conditioned medium of IL4R-Abx-treated M2 macrophages skewed M2 macrophages into the M1-like phenotype, in which an anti-HMGB1 antibody and a toll-like receptor 4 (TLR4) inhibitor induced a blockade. IL4R-Abx accumulated at tumors, heightened immune-stimulatory cells while reducing immune-suppressing cells, and hampered tumor growth and metastasis in mice more efficiently than Abx and Ctrl-Abx . Conclusions: These results indicate that IL4R-targeting allows enhancement of M2-macrophage shaping into M1-like phenotype by Abx through the ROS-HMGB1-TLR4 axis, improvement of antitumor immunity, and thereby inhibition of tumor growth and metastasis, presenting a new approach to cancer immunotherapy.

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Section: Discussionmentioning

confidence: 99%

IL4 receptor targeting enables nab-paclitaxel to enhance reprogramming of M2-type macrophages into M1-like phenotype via ROS-HMGB1-TLR4 axis and inhibition of tumor growth and metastasis

Vadevoo,

Kang,

Gunassekaran

et al. 2024

Theranostics

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“…Moreover, a recent study showed that the combination of the DNA methylation inhibitor 5-Aza-2’-deoxycytidine (5-Aza-dC) and the histone deacetylation inhibitor protomycin A were capable of reprogramming M2-like macrophages into M1-like macrophages, and resulted in a decrease of M2-related cytokines while an increase in M1-related ones. Furthermore, it was reported that the microRNA, miR-7083-5p, was a key modulator in this phenotype skewing as seen by its upregulation in M2-like macrophages after treatment, and its effect on inducing the M1-like phenotype after transfecting M2-like macrophages with this microRNA [ 131 ].…”

Section: Regulation Of Macrophage Polarizationmentioning

confidence: 99%

Deciphering the performance of macrophages in tumour microenvironment: a call for precision immunotherapy

Toledo,

Zhu Chen,

Paniagua-Sancho

et al. 2024

J Hematol Oncol

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Macrophages infiltrating tumour tissues or residing in the microenvironment of solid tumours are known as tumour-associated macrophages (TAMs). These specialized immune cells play crucial roles in tumour growth, angiogenesis, immune regulation, metastasis, and chemoresistance. TAMs encompass various subpopulations, primarily classified into M1 and M2 subtypes based on their differentiation and activities. M1 macrophages, characterized by a pro-inflammatory phenotype, exert anti-tumoural effects, while M2 macrophages, with an anti-inflammatory phenotype, function as protumoural regulators. These highly versatile cells respond to stimuli from tumour cells and other constituents within the tumour microenvironment (TME), such as growth factors, cytokines, chemokines, and enzymes. These stimuli induce their polarization towards one phenotype or another, leading to complex interactions with TME components and influencing both pro-tumour and anti-tumour processes.This review comprehensively and deeply covers the literature on macrophages, their origin and function as well as the intricate interplay between macrophages and the TME, influencing the dual nature of TAMs in promoting both pro- and anti-tumour processes. Moreover, the review delves into the primary pathways implicated in macrophage polarization, examining the diverse stimuli that regulate this process. These stimuli play a crucial role in shaping the phenotype and functions of macrophages. In addition, the advantages and limitations of current macrophage based clinical interventions are reviewed, including enhancing TAM phagocytosis, inducing TAM exhaustion, inhibiting TAM recruitment, and polarizing TAMs towards an M1-like phenotype. In conclusion, while the treatment strategies targeting macrophages in precision medicine show promise, overcoming several obstacles is still necessary to achieve an accessible and efficient immunotherapy.

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“…In fact, treatment of M2-type macrophages with a combination of the DNA methylation inhibitor 5-aza-dC and the histone deacetylation inhibitor trichostatin A decreases the levels of M2 macrophages, increasing the M1 subtype, and sensitizes the tumor cells to paclitaxel. Moreover, the combined treatment inhibits tumor growth and improves anti-tumor immunity in the TME [ 62 ].…”

Section: Crosstalk Between Apoptotic and Immune Cells Affects The Fat...mentioning

confidence: 99%

Apoptosis, a Metabolic “Head-to-Head” between Tumor and T Cells: Implications for Immunotherapy

Franzese,

Ancona,

Bianchi

et al. 2024

Cells

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Induction of apoptosis represents a promising therapeutic approach to drive tumor cells to death. However, this poses challenges due to the intricate nature of cancer biology and the mechanisms employed by cancer cells to survive and escape immune surveillance. Furthermore, molecules released from apoptotic cells and phagocytes in the tumor microenvironment (TME) can facilitate cancer progression and immune evasion. Apoptosis is also a pivotal mechanism in modulating the strength and duration of anti-tumor T-cell responses. Combined strategies including molecular targeting of apoptosis, promoting immunogenic cell death, modulating immunosuppressive cells, and affecting energy pathways can potentially overcome resistance and enhance therapeutic outcomes. Thus, an effective approach for targeting apoptosis within the TME should delicately balance the selective induction of apoptosis in tumor cells, while safeguarding survival, metabolic changes, and functionality of T cells targeting crucial molecular pathways involved in T-cell apoptosis regulation. Enhancing the persistence and effectiveness of T cells may bolster a more resilient and enduring anti-tumor immune response, ultimately advancing therapeutic outcomes in cancer treatment. This review delves into the pivotal topics of this multifaceted issue and suggests drugs and druggable targets for possible combined therapies.

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Epigenetic therapy reprograms M2-type tumor-associated macrophages into an M1-like phenotype by upregulating miR-7083-5p

Cited by 9 publications

References 41 publications

IL4 receptor targeting enables nab-paclitaxel to enhance reprogramming of M2-type macrophages into M1-like phenotype via ROS-HMGB1-TLR4 axis and inhibition of tumor growth and metastasis

IL4 receptor targeting enables nab-paclitaxel to enhance reprogramming of M2-type macrophages into M1-like phenotype via ROS-HMGB1-TLR4 axis and inhibition of tumor growth and metastasis

Deciphering the performance of macrophages in tumour microenvironment: a call for precision immunotherapy

Apoptosis, a Metabolic “Head-to-Head” between Tumor and T Cells: Implications for Immunotherapy

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