Boosting anti-PD-1 therapy with metformin-loaded macrophage-derived microparticles

Wei, Zhaohan; Zhang, Xiaoqiong; Yong, Tuying; Bie, Nana; Zhan, Guiting; Li, Xin; Liang, Qingle; Li, Jianye; Yu, Jingjing; Huang, Gang; Yan, Yuchen; Zhang, Zelong; Zhang, Bixiang; Gan, Lu; Huang, Bo; Yang, Xiangliang

doi:10.1038/s41467-020-20723-x

Cited by 211 publications

(195 citation statements)

References 62 publications

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“…Similarly, Zhang et al described a nanocarrier-based delivery system for loading interferon regulatory factor 5 and IKKβ to TAMs to reverse M2-like TAMs into M1-like phenotypes without causing in vivo systemic toxicity [ 122 ]. In addition, Wei et al treated macrophages with mannose (Man)-modified macrophage-derived MPs, which are carriers for the targeted delivery of metformin (called Met@Man-MPs) to M2-like TAMs [ 123 ]. They showed that Met@Man-MPs efficiently reset TAMs toward the M1 phenotype to inhibit tumor growth.…”

Section: Immunotherapy and Tam-targeted Therapymentioning

confidence: 99%

“…They showed that Met@Man-MPs efficiently reset TAMs toward the M1 phenotype to inhibit tumor growth. Met@Man-MPs significantly improved the tumor immunosuppressive microenvironment and enhanced CD8+ T cell infiltration into the tumor interior by restoring macrophage-induced recruitment of CD8+ T cells and Man-MP-induced tumor ECM degradation because macrophages express matrix metalloproteinases (MMP) [ 123 ]. In addition, the utilization of normal MSCs to modulate TAM polarization is another promising therapeutic strategy.…”

Section: Immunotherapy and Tam-targeted Therapymentioning

confidence: 99%

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The Impact of the Tumor Microenvironment on Macrophage Polarization in Cancer Metastatic Progression

Wang

Yung

Ngan

et al. 2021

IJMS

128

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Rather than primary solid tumors, metastasis is one of the hallmarks of most cancer deaths. Metastasis is a multistage event in which cancer cells escape from the primary tumor survive in the circulation and disseminate to distant sites. According to Stephen Paget's “Seed and Soil” hypothesis, metastatic capacity is determined not only by the internal oncogenic driving force but also by the external environment of tumor cells. Throughout the body, macrophages are required for maintaining tissue homeostasis, even in the tumor milieu. To fulfill these multiple functions, macrophages are polarized from the inflammation status (M1-like) to anti-inflammation status (M2-like) to maintain the balance between inflammation and regeneration. However, tumor cell-enforced tumor-associated macrophages (TAMs) (a high M2/M1 ratio status) are associated with poor prognosis for most solid tumors, such as ovarian cancer. In fact, clinical evidence has verified that TAMs, representing up to 50% of the tumor mass, exert both protumor and immunosuppressive effects in promoting tumor metastasis through secretion of interleukin 10 (IL10), transforming growth factor β (TGFβ), and VEGF, expression of PD-1 and consumption of arginine to inhibit T cell anti-tumor function. However, the underlying molecular mechanisms by which the tumor microenvironment favors reprogramming of macrophages to TAMs to establish a premetastatic niche remain controversial. In this review, we examine the latest investigations of TAMs during tumor development, the microenvironmental factors involved in macrophage polarization, and the mechanisms of TAM-mediated tumor metastasis. We hope to dissect the critical roles of TAMs in tumor metastasis, and the potential applications of TAM-targeted therapeutic strategies in cancer treatment are discussed.

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Section: Immunotherapy and Tam-targeted Therapymentioning

confidence: 99%

Section: Immunotherapy and Tam-targeted Therapymentioning

confidence: 99%

The Impact of the Tumor Microenvironment on Macrophage Polarization in Cancer Metastatic Progression

Wang

Yung

Ngan

et al. 2021

IJMS

128

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“…However, the anti-tumor effect was insufficient for further evaluation, which might be because most recruited patients were resistant to the PD-1 antibody ( 79 ). Recently, mannose-modified macrophage-derived microparticles loaded with metformin have been developed to reprogram M2 to M1 macrophages, which can synergistically enhance anti-PD-1 therapy ( 80 ).…”

Section: Macrophage Reprogramming and Pd-l1/pd-1 Blockade In Cancer Therapymentioning

confidence: 99%

Defects in Macrophage Reprogramming in Cancer Therapy: The Negative Impact of PD-L1/PD-1

et al. 2021

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Classically activated M1 macrophages and alternatively activated M2 macrophages are two polarized subsets of macrophages at the extreme ends of a constructed continuum. In the field of cancer research, M2 macrophage reprogramming is defined as the repolarization of pro-tumoral M2 to anti-tumoral M1 macrophages. It is known that colony-stimulating factor 1 (CSF1)/CSF1 receptor (CSF1R) and CSF2/CSF2R signaling play important roles in macrophage polarization. Targeting CSF1/CSF1R for M2 macrophage reprogramming has been widely performed in clinical trials for cancer therapy. Other targets for M2 macrophage reprogramming include Toll-like receptor 7 (TLR7), TLR8, TLR9, CD40, histone deacetylase (HDAC), and PI3Kγ. Although macrophages are involved in innate and adaptive immune responses, M1 macrophages are less effective at phagocytosis and antigen presenting, which are required properties for the activation of T cells and eradication of cancer cells. Similar to T and dendritic cells, the “functionally exhausted” status might be attributed to the high expression of programmed death-ligand 1 (PD-L1) or programmed cell death protein 1 (PD-1). PD-L1 is expressed on both M1 and M2 macrophages. Macrophage reprogramming from M2 to M1 might increase the expression of PD-L1, which can be transcriptionally activated by STAT3. Macrophage reprogramming or PD-L1/PD-1 blockade alone is less effective in the treatment of most cancers. Since PD-L1/PD-1 blockade could make up for the defect in macrophage reprogramming, the combination of macrophage reprogramming and PD-L1/PD-1 blockade might be a novel treatment strategy for cancer therapy.

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“…A similar result was seen in IL-4-stimulated RAW264.7 cells, murine bone marrow-derived macrophages, THP-1-originated macrophages, and human peripheral blood monocyte-derived macrophages, where mannose-modified, macrophage-derived microparticles loaded with metformin converted the M2 phenotype toward M1. In this study, such microparticles loaded with metformin were also effective in an animal model to reprogram the tumor immune microenvironment [ 139 ]. In addition, metformin was reported to act on the cancer cell to reduce the M2 polarization of the tumor-associated macrophage.…”

Section: Metformin On the Immune Population That May Indirectly Inhibit Nash-related Hcc Developmentmentioning

confidence: 99%

Metformin Actions on the Liver: Protection Mechanisms Emerging in Hepatocytes and Immune Cells against NASH-Related HCC

Zhang

Wang

Xiao

2021

IJMS

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Nonalcoholic fatty liver disease (NAFLD) is strongly linked to the global epidemic of obesity and type 2 diabetes mellitus (T2DM). Notably, NAFLD can progress from the mildest form of simple steatosis to nonalcoholic steatohepatitis (NASH) that increases the risk for hepatocellular carcinoma (HCC), which is a malignancy with a dismal prognosis and rising incidence in the United States and other developed counties, possibly due to the epidemic of NAFLD. Metformin, the first-line drug for T2DM, has been suggested to reduce risks for several types of cancers including HCC and protect against NASH-related HCC, as revealed by epidemical studies on humans and preclinical studies on animal models. This review focuses on the pathogenesis of NASH-related HCC and the mechanisms by which metformin inhibits the initiation and progression of NASH-related HCC. Since the functional role of immune cells in liver homeostasis and pathogenesis is increasingly appreciated in developing anti-cancer therapies on liver malignancies, we discuss both the traditional targets of metformin in hepatocytes and the recently defined effects of metformin on immune cells.

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Boosting anti-PD-1 therapy with metformin-loaded macrophage-derived microparticles

Cited by 211 publications

References 62 publications

The Impact of the Tumor Microenvironment on Macrophage Polarization in Cancer Metastatic Progression

The Impact of the Tumor Microenvironment on Macrophage Polarization in Cancer Metastatic Progression

Defects in Macrophage Reprogramming in Cancer Therapy: The Negative Impact of PD-L1/PD-1

Metformin Actions on the Liver: Protection Mechanisms Emerging in Hepatocytes and Immune Cells against NASH-Related HCC

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