M2-Like Tumor-Associated Macrophage-Targeted Codelivery of STAT6 Inhibitor and IKKβ siRNA Induces M2-to-M1 Repolarization for Cancer Immunotherapy with Low Immune Side Effects

Xiao, Hong; Guo, Yu; Li, Bo; Li, Xiaoxia; Wang, Yong; Han, Shisong; Cheng, Du; Shuai, Xintao

doi:10.1021/acscentsci.9b01235

Cited by 162 publications

(112 citation statements)

References 49 publications

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“…Lee et al used a mixed peptide MEL-DKLA to induce the death of M2 macrophages, resulting in a slower tumor growth rate [ 29 ]. Xiao et al developed a smart nanodrug that can trigger active targeting of M2-like macrophages only in acidic TME, repolarizing M2-like macrophages into M1 macrophages for cancer immunotherapy with low side effects [ 30 ]. Klichinsky et al genetically engineered macrophages using chimeric antigen receptors.…”

Section: Discussionmentioning

confidence: 99%

Coexpressed Genes That Promote the Infiltration of M2 Macrophages in Melanoma Can Evaluate the Prognosis and Immunotherapy Outcome

Yan

Wang

et al. 2021

Journal of Immunology Research

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Purpose. To improve immunotherapy efficacy for melanoma, a coexpression network and key genes of M2 macrophages in melanoma were explored. A prognostic risk assessment model was established for M2-related coexpressed genes, and the role of M2 macrophages in the immune microenvironment of melanoma was elucidated. Method. We obtained mRNA data from melanoma and peritumor tissue samples from The Cancer Genome Atlas-skin cutaneous melanoma (TCGA-SKCM). Then, we used CIBERSORT to calculate the proportion of M2 macrophage cells. A coexpression module most related to M2 macrophages in TCGA-SKCM was determined by analyzing the weighted gene coexpression network, and a coexpression network was established. After survival analysis, factors with significant results were incorporated into a Cox regression analysis to establish a model. The model’s essential genes were analyzed using functional enrichment, GSEA, and subgroup and total carcinoma. Finally, external datasets GSE65904 and GSE78220 were used to verify the prognostic risk model. Results. The yellow-green module was the coexpression module most related to M2 macrophages in TCGA-SKCM; NOTCH3, DBN1, KDELC2, and STAB1 were identified as the essential genes that promoted the infiltration of M2 macrophages in melanoma. These genes are concentrated in antigen treatment and presentation, chemokine, cytokine, the T cell receptor pathway, and the IFN-γ pathway. These factors were analyzed for survival, and factors with significant results were included in a Cox regression analysis. According to the methods, a model related to M2-TAM coexpressed gene was established, and the formula was risk score = 0.25 ∗ NOTCH 3 + 0.008 ∗ DBN 1 − 0.031 ∗ KDELC 2 − 0.032 ∗ STAB 1 . The new model was used to perform subgroup evaluation and external queue validation. The results showed good prognostic ability. Conclusion. We proposed a Cox proportional hazards regression model associated with coexpression genes of melanoma M2 macrophages that may provide a measurement method for generating prognosis scores in patients with melanoma. Four genes coexpressed with M2 macrophages were associated with high levels of infiltration of M2 macrophages. Our findings may provide significant candidate biomarkers for the treatment and monitoring of melanoma.

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Section: Discussionmentioning

confidence: 99%

Coexpressed Genes That Promote the Infiltration of M2 Macrophages in Melanoma Can Evaluate the Prognosis and Immunotherapy Outcome

Yan

Wang

et al. 2021

Journal of Immunology Research

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“…Gene therapeutic agents (e.g., siRNAs, mRNAs) are powerful tools to modulate macrophage function 12 , 13 . Nevertheless, viruses, a common gene vector, may cause a series of side effects, such as insertion mutagenesis and an inflammatory response, which makes viral vectors ineligible for in vivo therapeutic application 14 .…”

Section: Introductionmentioning

confidence: 99%

Suppressing Sart1 to modulate macrophage polarization by siRNA-loaded liposomes: a promising therapeutic strategy for pulmonary fibrosis

et al. 2021

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Idiopathic pulmonary fibrosis (IPF) is a chronic and diffuse form of interstitial lung disease of unknown etiology with a fatal outcome. Although various strategies for IPF have been developed over the last few decades, no significant positive impact on the prognosis of IPF has been observed. According to the current paradigm, macrophages have been recognized to play a significant role in IPF pathogenesis. Here, we report a potential nanomedicine-based gene therapy for IPF based on regulate macrophage polarization. Method: C57BL/6 mice were obtained and used to establish a bleomycin (BLM)-induced pulmonary fibrosis animal model, and Sart1 siRNA-loaded liposomes were designed for in vivo experiment. The experimental animals were administered BLM intratracheally on day 0 and treated with Sart1 siRNA on days 14 and 17. In the in vitro experiment, we further examined the function of Sart1 in macrophages. Results: Our data indicated that the liposomes could passively target the fibrotic area in the lung and efficiently accumulate in macrophages. The suppression of Sart1 by siRNA-loaded liposomes significantly protected mice against BLM-induced lung injury and fibrosis, which was attributed to attenuated M2 macrophage infiltration in the lung. Conclusion: Our study provides a valuable reference for modulating macrophage polarization and a promising strategy for the treatment of pulmonary fibrosis in clinical settings.

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“…Under hypoxic conditions, anti-P-gp siRNA delivered by PAPD showed up to a 60% P-gp downregulation. Recently, a dual pH-sensitive micellar nanodrug that can achieve the codelivery of IKKβ siRNA and STAT6 inhibitor AS1517499 via the M2-targeting peptide was reported by Xiao et al [ 83 ]. The M2-targeting peptides were hidden by the pH-sheddable PEG corona so that the micellar nanodrug could efficiently reduce the immune side effects because of the acidic tumor microenvironment.…”

Section: Protective Carriers For Sirna Deliverymentioning

confidence: 99%

Nanoparticles as Drug Delivery Systems of RNAi in Cancer Therapy

Gao

Kuang

et al. 2021

Molecules

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RNA interference (RNAi) can mediate gene-silencing by knocking down the expression of a target gene via cellular machinery with much higher efficiency in contrast to other antisense-based approaches which represents an emerging therapeutic strategy for combating cancer. Distinct characters of nanoparticles, such as distinctive size, are fundamental for the efficient delivery of RNAi therapeutics, allowing for higher targeting and safety. In this review, we present the mechanism of RNAi and briefly describe the hurdles and concerns of RNAi as a cancer treatment approach in systemic delivery. Furthermore, the current nanovectors for effective tumor delivery of RNAi therapeutics are classified, and the characteristics of different nanocarriers are summarized.

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M2-Like Tumor-Associated Macrophage-Targeted Codelivery of STAT6 Inhibitor and IKKβ siRNA Induces M2-to-M1 Repolarization for Cancer Immunotherapy with Low Immune Side Effects

Cited by 162 publications

References 49 publications

Coexpressed Genes That Promote the Infiltration of M2 Macrophages in Melanoma Can Evaluate the Prognosis and Immunotherapy Outcome

Coexpressed Genes That Promote the Infiltration of M2 Macrophages in Melanoma Can Evaluate the Prognosis and Immunotherapy Outcome

Suppressing Sart1 to modulate macrophage polarization by siRNA-loaded liposomes: a promising therapeutic strategy for pulmonary fibrosis

Nanoparticles as Drug Delivery Systems of RNAi in Cancer Therapy

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