Lachnum polysaccharide suppresses S180 sarcoma by boosting anti-tumor immune responses and skewing tumor-associated macrophages toward M1 phenotype

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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Elevated expression of IL-10RB acts as an independent unfavorable prognostic marker and predicts the polarization of tumor-associated macrophages in glioma

10.21203/rs.3.rs-364328/v1 ◽

2021 ◽

Author(s):

Yaqiong Fan ◽

Yichen Peng ◽

Feng Chen ◽

Wenbin Li

Keyword(s):

Immune Responses ◽

Prognostic Marker ◽

Poor Prognosis ◽

Immune Cell ◽

Cox Regression ◽

Interleukin 10 ◽

Immune Checkpoints ◽

Marker Genes ◽

Tumor Associated Macrophages ◽

Cox Regression Analysis

Abstract Background: Interleukin-10 receptor B (IL10RB) is a subunit of the interleukin-10 receptor. As an important part of the interleukin-10 signaling pathway, IL10RB plays an essential role in the regulation of the immune response. However, studies of IL10RB in glioma are rare. The present study aimed to investigate the potential role of IL10RB in glioma.Methods: 611 glioma samples in TCGA dataset and 310 glioma samples in CGGA dataset were download and organized, then analyzed the clinical expression characteristics and prognostic value of IL10RB as well as its correlation with immune cell infiltration in these samples using R. Results: IL10RB expression was significantly higher in the glioma tissues than in the normal tissues and increased in gliomas, especially with malignant phenotype. The Kaplan-Meier survival analysis and Cox regression analysis indicated that IL10RB was significantly associated with poor prognosis in patients with glioma and could be used as an independent prognostic marker. Further functional analysis suggested that IL10RB was involved in immune responses, and high expression of IL10RB in the glioma tissue resulted in more infiltrated immune cells, especially macrophages. Moreover, IL10RB was found to be strongly correlated with marker genes of tumor-associated macrophages (TAMs) and M2 macrophages, but low or even no correlation with marker genes of M1 macrophages. In addition, there was also a significant association between IL10RB and immune checkpoints that suppress effective antitumor immune responses.Conclusions: Our results demonstrated that high expressed IL10RB was associated with the malignant progression of gliomas and poor prognosis, and it might be involved in the polarization of macrophages which play a crucial role in the immunosuppressive response of gliomas.

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Perforin-2 limits pathogen proliferation at the maternal-fetal interface

10.1101/2020.05.20.107193 ◽

2020 ◽

Author(s):

Petoria Gayle ◽

Vanessa McGaughey ◽

Rosmely Hernandez ◽

Marina Wylie ◽

Rachel C. Colletti ◽

...

Keyword(s):

Immune Responses ◽

Immune Cells ◽

Host Response ◽

Protective Role ◽

High Dose ◽

High Burden ◽

Mouse Placenta ◽

Splenic Macrophages ◽

M1 Phenotype ◽

Maternal Fetal Interface

AbstractPlacental immune responses are highly regulated to strike a balance between protection and tolerance. For relatively mild infections, protection encompasses both the mother and fetus; however, during worsening conditions, protection becomes exclusively reserved for the mother. Previously, we and others have shown that the host factor Perforin-2 plays a central role in protecting mice and cells against infection. Here, we analyzed Perforin-2 activity in the mouse placenta to determine whether Perforin-2 plays a similarly protective role. We show that Perforin-2 is critical for inhibiting Listeria monocytogenes colonization of the placenta and fetus and that this protection is due to both maternal and fetal-encoded Perforin-2. Perforin-2 mRNA is readily detectable in individual immune cells of the decidua and these levels are further enhanced specifically in decidual macrophages during high-dose infections that result in fetal expulsion. Unexpectedly, inductive Perforin-2 expression in decidual macrophages did not occur during milder infections in which fetal viability remained intact. This pattern of expression significantly differed from that observed in splenic macrophages in which inductive Perforin-2 expression was observed in both high and mild infection conditions. In the placenta, inductive Perforin-2 expression in decidual macrophages was co-incident with their polarization from a M2 to M1 phenotype that normally occurs in the placenta during high-burden infections. Our results suggest that Perforin-2 is part of a host response that is protective either for both the mother and fetus in milder infections or exclusively for the mother during high-dose infections.

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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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Mannose receptor (CD206) activation in tumor-associated macrophages enhances adaptive and innate antitumor immune responses

Science Translational Medicine ◽

10.1126/scitranslmed.aax6337 ◽

2020 ◽

Vol 12 (530) ◽

pp. eaax6337 ◽

Cited By ~ 17

Author(s):

Jesse M. Jaynes ◽

Rushikesh Sable ◽

Michael Ronzetti ◽

Wendy Bautista ◽

Zachary Knotts ◽

...

Keyword(s):

Immune Response ◽

Immune Responses ◽

Tumor Growth ◽

Cancer Progression ◽

Selective Reduction ◽

Mannose Receptor ◽

Tumor Associated Macrophages ◽

Host Defense Peptides ◽

Surface Receptors ◽

Effective Combination

Solid tumors elicit a detectable immune response including the infiltration of tumor-associated macrophages (TAMs). Unfortunately, this immune response is co-opted into contributing toward tumor growth instead of preventing its progression. We seek to reestablish an antitumor immune response by selectively targeting surface receptors and endogenous signaling processes of the macrophage subtypes driving cancer progression. RP-182 is a synthetic 10-mer amphipathic analog of host defense peptides that selectively induces a conformational switch of the mannose receptor CD206 expressed on TAMs displaying an M2-like phenotype. RP-182–mediated activation of this receptor in human and murine M2-like macrophages elicits a program of endocytosis, phagosome-lysosome formation, and autophagy and reprograms M2-like TAMs to an antitumor M1-like phenotype. In syngeneic and autochthonous murine cancer models, RP-182 suppressed tumor growth, extended survival, and was an effective combination partner with chemo- or immune checkpoint therapy. Antitumor activity of RP-182 was also observed in CD206high patient-derived xenotransplantation models. Mechanistically, via selective reduction of immunosuppressive M2-like TAMs, RP-182 improved adaptive and innate antitumor immune responses, including increased cancer cell phagocytosis by reprogrammed TAMs.

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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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