Peptide-guided resiquimod-loaded lignin nanoparticles convert tumor-associated macrophages from M2 to M1 phenotype for enhanced chemotherapy

Abstract There is increasing interest in depleting or repolarizing tumor-associated macrophages (TAMs) to generate a pro-inflammatory effect. However, TAMs usually display an immunosuppressive M2-like phenotype in tumor microenvironment. Apparently, developing a macrophage targeting delivery system with immunomodulatory agents is urgent. In the study, an efficient siRNAs and CpG ODNs delivery system (CpG-siRNA-tFNA) was prepared with nucleic acid stepwise self-assembled. The tFNA composed of CpG ODNs and siRNAs showed a higher stability and an enhanced cellular uptake efficiency. Moreover, the CpG-siRNA-tFNA effectively reprogrammed TAMs toward M1 phenotype polarization with increased pro-inflammatory cytokines secretion and NF-κB signal pathways activation, which triggers dramatical antitumor immune responses. Hence, we have developed an efficient and reliable TAM-targeted therapeutic with immunomodulatory agents for for clinical applications.

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M1 Polarized Tumor-Associated Macrophages (TAMs) as Promising Prognostic Signature in Stage I–II Gastric Adenocarcinomas

Gastrointestinal Disorders ◽

10.3390/gidisord3040020 ◽

2021 ◽

Vol 3 (4) ◽

pp. 207-217

Author(s):

Antonio Ieni ◽

Rosario Alberto Caruso ◽

Cristina Pizzimenti ◽

Giuseppe Giuffrè ◽

Eleonora Irato ◽

...

Keyword(s):

Perineural Invasion ◽

Giant Cells ◽

Tumor Location ◽

Stage I ◽

Case Group ◽

Tumor Associated Macrophages ◽

M1 Macrophages ◽

Gastric Adenocarcinomas ◽

M1 Phenotype ◽

Clinicopathological Significance

Tumor-associated macrophages (TAMs) may be noticed in gastric carcinomas (GC), but their clinicopathological significance has not been yet explored. From a histological review of 400 cases of tubular/papillary adenocarcinomas, 24 cases of stage I–II gastric adenocarcinomas with intraglandular and stromal TAMs were identified. Their clinicopathological features were compared with 72 pT-matched as well as stage-matched control cases of adenocarcinomas without TAMs. TAMs present in GC cases were present either in glands or in neoplastic stroma, showing an immunoreactivity for CD68 and CD80; sometimes, they were organized in mature granulomas with occasional giant cells. Therefore, the stained TAMs were reminiscent of a specific polarized macrophage M1 phenotype; however, in any case of our cohort, no M2 phenotype macrophages were documented by CD 163 and CD 204 immunostainings. Statistically, no significant differences in age, gender, tumor location, size, and lymphovascular and perineural invasion between the case group with TAMs and pT- as well as stage-matched controls were reported; furthermore, the case group showed lower frequency of lymph node metastasis (p = 0.02). In addition, a significantly different clinical course and overall survival rate were also observed in gastric adenocarcinomas with M1 TAMs (p = 0.02) in comparison to controls. These results suggest that tumor-associated M1 macrophages are related to a quite indolent growth and a better prognosis of patients with this peculiar variant of gastric adenocarcinomas.

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Tumor-Associated Macrophages as Potential Targets for Anti-Cancer Activity of Marine Invertebrate-Derived Compounds

Current Pharmaceutical Design ◽

10.2174/1381612827666210319125652 ◽

2021 ◽

Vol 27 ◽

Author(s):

Lyudmila S. Dolmatova ◽

Igor Yu. Dolmatov

Keyword(s):

Marine Invertebrates ◽

Marine Invertebrate ◽

Mechanisms Of Action ◽

Tumor Associated Macrophages ◽

Drug Candidates ◽

Promote Tumor Growth ◽

Anti Cancer ◽

M1 Phenotype ◽

Marine Compounds ◽

Tumor Growth And Metastasis

: Tumor-associated macrophages (TAMs) are M2 phenotype dominant and promote tumor growth and metastasis. The new cancer treatment strategy includes TAM targeting and is aimed primarily at reprogramming TAMs toward the M1 phenotype or reducing the number and activity of M2 macrophages. Several marine invertebrate-derived drugs, combining efficacy and a low level of side effects, were approved for use in the cancer therapy. The mechanisms of action of some of them include TAM targeting. The review includes data showing immunomodulatory properties of these already approved anticancer drugs and drug candidates in clinical development which additionally incorporate data from screening studies of new substances from marine invertebrates. Based on screening data, the most promising marine compounds for cancer immunotherapy are supposed.

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Chloroquine modulates antitumor immune response by resetting tumor-associated macrophages toward M1 phenotype

Nature Communications ◽

10.1038/s41467-018-03225-9 ◽

2018 ◽

Vol 9 (1) ◽

Cited By ~ 75

Author(s):

Degao Chen ◽

Jing Xie ◽

Roland Fiskesund ◽

Wenqian Dong ◽

Xiaoyu Liang ◽

...

Keyword(s):

Immune Response ◽

Antitumor Immune Response ◽

Tumor Associated Macrophages ◽

M1 Phenotype

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Intratumoral Delivery of IL-21 Overcomes Anti-Her2/Neu Resistance through Shifting Tumor-Associated Macrophages from M2 to M1 Phenotype

The Journal of Immunology ◽

10.4049/jimmunol.1402603 ◽

2015 ◽

Vol 194 (10) ◽

pp. 4997-5006 ◽

Cited By ~ 45

Author(s):

Meng Xu ◽

Mingyue Liu ◽

Xuexiang Du ◽

Sirui Li ◽

Hang Li ◽

...

Keyword(s):

Tumor Associated Macrophages ◽

M1 Phenotype ◽

Intratumoral Delivery

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MR Susceptibility Imaging for Detection of Tumor-Associated Macrophages in Glioblastoma

10.21203/rs.3.rs-1017881/v1 ◽

2021 ◽

Author(s):

Amir Nazem ◽

Samantha Guiry ◽

Mehrdad Pourfathi ◽

Jeffrey B. Ware ◽

Hannah Anderson ◽

...

Keyword(s):

Ex Vivo ◽

Imaging Biomarker ◽

Tumor Associated Macrophages ◽

Intracellular Iron ◽

Positive Correlation ◽

Non Invasive ◽

Cell Counts ◽

Susceptibility Maps ◽

Invasive Method ◽

M1 Phenotype

Abstract Purpose Tumor-associated macrophages (TAMs) are a key component of glioblastoma (GBM) microenvironment. Considering the differential role of different TAM phenotypes in iron metabolism with the M1 phenotype storing intracellular iron, and M2 phenotype releasing iron in the tumor microenvironment, we investigated MRI to quantify iron as an imaging biomarker for TAMs in GBM patients. Methods 21 adult patients with GBM underwent a 3D single echo gradient echo MRI sequence and quantitative susceptibility maps were generated. In 3 subjects, ex vivo imaging of surgical specimens was performed on a 9.4 Tesla MRI using 3D multi-echo GRE scans, and R2* (1/T2*) maps were generated. Each specimen was stained with hematoxylin and eosin, as well as CD68, CD86, CD206, and L-Ferritin. Results Significant positive correlation was observed between mean susceptibility for the tumor enhancing zone and the L-ferritin positivity percent (r =0.56, p=0.018) and the combination of tumor’s enhancing zone and necrotic core and the L-Ferritin positivity percent (r=0.72; p=0.001). The mean susceptibility significantly correlated with positivity percent for CD68 (ρ = 0.52, p=0.034) and CD86 (r=0.7 p=0.001), but not for CD206 (ρ = 0.09; p=0.7). There was a positive correlation between mean R2* values and CD68 positive cell counts (r =0.6, p=0.016). Similarly, mean R2* values significantly correlated with CD86 (r=0.54, p=0.03) but not with CD206 (r=0.15, p=0.5). Conclusion MR quantitative susceptibility mapping can quantify the iron content of GBM and provide a non-invasive method for TAM quantification and phenotyping.

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Abstract 439: BCL-2 inhibitor APG-2575 promotes anti-tumor efficacy of immune checkpoint blockade through converting tumor-associated macrophages into M1 phenotype in non-small cell lung cancer

10.1158/1538-7445.am2021-439 ◽

2021 ◽

Author(s):

Fan Luo ◽

Fei Teng Lu ◽

Miao Zhen Qiu ◽

Wen Tao Pan ◽

Lin Zhang ◽

...

Keyword(s):

Lung Cancer ◽

Small Cell Lung Cancer ◽

Cell Lung Cancer ◽

Immune Checkpoint ◽

Immune Checkpoint Blockade ◽

Small Cell ◽

Checkpoint Blockade ◽

Small Cell Lung ◽

Tumor Associated Macrophages ◽

M1 Phenotype

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Mushroomβ-Glucan May Immunomodulate the Tumor-Associated Macrophages in the Lewis Lung Carcinoma

BioMed Research International ◽

10.1155/2015/604385 ◽

2015 ◽

Vol 2015 ◽

pp. 1-15 ◽

Cited By ~ 4

Author(s):

Wan-Jhen Wang ◽

Yu-Sheng Wu ◽

Sherwin Chen ◽

Chi-Feng Liu ◽

Shiu-Nan Chen

Keyword(s):

Mrna Expression ◽

Immune Suppression ◽

Ganoderma Lucidum ◽

Tumor Model ◽

Lewis Lung ◽

Tumor Associated Macrophages ◽

Antrodia Camphorata ◽

Beta Glucan ◽

M1 Phenotype ◽

Cox 2

The present study showed that oral mushroom beta-glucan treatment significantly increased IFN-γmRNA expression but significantly reduced COX-2 mRNA expression within the lung. For LLC tumor model, oralGanoderma lucidumorAntrodia camphoratapolysaccharides treatments significantly reduced TGF-βproduction in serum. In addition, IL-12 and IFN-γmRNA expression were significantly increased, but IL-6, IL-10, COX-2, and TGF-βmRNA expression were substantially following oral mushroom polysaccharides treatments. The study highlights the efficacious effect of mushroom polysaccharides for ameliorating the immune suppression in the tumor microenvironment. Increased M1 phenotype of tumor-associated macrophages and attenuated M2 phenotype of tumor-associated macrophages could be achieved by ingesting mushroom polysaccharides.

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Reprograming of Tumor-Associated Macrophages in Breast Tumor-Bearing Mice under Chemotherapy by Targeting Heme Oxygenase-1

Antioxidants ◽

10.3390/antiox10030470 ◽

2021 ◽

Vol 10 (3) ◽

pp. 470

Author(s):

Seung Hyeon Kim ◽

Su-Jung Kim ◽

Jeongmin Park ◽

Yeonsoo Joe ◽

So Eui Lee ◽

...

Keyword(s):

Tumor Cell ◽

Heme Oxygenase ◽

Breast Tumor ◽

Heme Oxygenase 1 ◽

M2 Macrophage ◽

Cell Debris ◽

Tumor Associated Macrophages ◽

Tumor Bearing ◽

M1 Phenotype ◽

The Impact

Tumor-associated macrophages (TAMs) represent one of the most abundant components of the tumor microenvironment and play important roles in tumor development and progression. TAMs display plasticity and functional heterogeneity as reflected by distinct phenotypic subsets. TAMs with an M1 phenotype have proinflammatory and anti-tumoral properties whereas M2-like TAMs exert anti-inflammatory and pro-tumoral functions. Tumor cell debris generated during chemotherapy can stimulate primary tumor growth and recurrence. According to our previous study, phagocytic engulfment of breast tumor cell debris by TAMs attenuated chemotherapeutic efficacy through the upregulation of heme oxygenase-1 (HO-1). To verify the impact of HO-1 upregulation on the profile of macrophage polarization during cytotoxic therapy, we utilized a syngeneic murine breast cancer (4T1) model in which tumor bearing mice were treated with paclitaxel (PTX). PTX treatment markedly downregulated the surface expression of the M1 marker CD86 in infiltrated TAMs. Notably, there were significantly more cytotoxic CD8+ T cells in tumors of mice treated with PTX plus the HO-1 inhibitor, zinc protophorphyrin IX (ZnPP) than in mice treated with PTX alone. Interestingly, the tumor-inhibiting efficacy of PTX and ZnPP co-treatment was abrogated when macrophages were depleted by clodronate liposomes. Macrophage depletion also decreased the intratumoral CD8+ T cell population and downregulated the expression of Cxcl9 and Cxcl10. The expression of the M1 phenotype marker, CD86 was higher in mice injected with PTX plus ZnPP than that in mice treated with PTX alone. Conversely, the PTX-induced upregulation of the M2 marker gene, Il10 in CD11b+ myeloid cells from 4T1 tumor-bearing mice treated was dramatically reduced by the administration of the HO-1 inhibitor. Genetic ablation of HO-1 abolished the inhibitory effect of 4T1 tumor cell debris on expression of M1 marker genes, Tnf and Il12b, in LPS-stimulated BMDMs. HO-1-deficient BMDMs exposed to tumor cell debris also exhibited a diminished expression of the M2 macrophage marker, CD206. These findings, taken all together, provide strong evidence that HO-1 plays a pivotal role in the transition of tumor-inhibiting M1-like TAMs to tumor-promoting M2-like ones during chemotherapy.

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