Speaker
Description
Macrophages are innate immune cells with a wide range of functional capacities(Wu et al., 2021). They have been broadly classified into M1 or M2 phenotypes based on environmental signals. Due to variation in such regulatory cues, these macrophages are thought to also show states that are intermediate within a spectrum that has M1 and M2 at its two extremes(Karnevi et al., 2014). However, across all these studies, characterization for hybrid macrophages is not consistent due to overlapping macrophage markers. How hybrid macrophages arise, how stable these states are, how easy is it for them to transition from, or to M0, M1, or M2 states, and how is their stability reinforced or attenuated by the distinct secretory states remains poorly understood. To address these set of problems, we define the hybrid macrophage phenotype based on gene regulatory network (GRN) information at intracellular scale. Our findings reveal a 'teams' structure as an emergent property of the macrophage GRN. Perturbation analysis was done with M1 and M2 as initial states and as two different cases. In one node perturbation, the system is unable to switch its phenotype in either case, but in some two and three-node combinations, the system can switch to hybrid phenotype. Furthermore, overexpression analysis was done, where STAT3 and STAT1 combination was specifically observed to give rise to the most hybrid populations. The phenotypic distribution obtained from the Boolean framework was then validated using RAndom CIrcuit PErturbation (RACIPE). The distribution of steady state in overexpression analysis using RACIPE was consistent with the Boolean framework, making the distribution of steady states a robust dynamical property of the network.
Bibliography
@ARTICLE{Wu2021-id,
title = "The {M1/M2} spectrum and plasticity of malignant pleural
effusion-macrophage in advanced lung cancer",
author = "Wu, Ming-Fang and Lin, Chih-An and Yuan, Tzu-Hang and Yeh,
Hsiang-Yuan and Su, Sheng-Fang and Guo, Chin-Lin and Chang,
Gee-Chen and Li, Ker-Chau and Ho, Chao-Chi and Chen, Huei-Wen",
abstract = "BACKGROUND: Malignant pleural effusion (MPE)-macrophage
(M$\varphi$) of lung cancer patients within unique M1/M2
spectrum showed plasticity in M1-M2 transition. The M1/M2
features of MPE-M$\varphi$ and their significance to patient
outcomes need to be clarified; furthermore, whether
M1-repolarization could benefit treatment remains unclear.
METHODS: Total 147 stage-IV lung adenocarcinoma patients
undergoing MPE drainage were enrolled for profiling and
validation of their M1/M2 spectrum. In addition, the
MPE-M$\varphi$ signature on overall patient survival was
analyzed. The impact of the M1-polarization strategy of
patient-derived MPE-M$\varphi$ on anti-cancer activity was
examined. RESULTS: We found that MPE-M$\varphi$ expressed both
traditional M1 (HLA-DRA) and M2 (CD163) markers and showed a
wide range of M1/M2 spectrum. Most of the MPE-M$\varphi$
displayed diverse PD-L1 expression patterns, while the low PD-L1
expression group was correlated with higher levels of IL-10.
Among these markers, we identified a novel two-gene
MPE-M$\varphi$ signature, IL-1$\beta$ and TGF-$\beta$1,
representing the M1/M2 tendency, which showed a strong
predictive power in patient outcomes in our MPE-M$\varphi$
patient cohort (N = 60, p = 0.013) and The Cancer Genome Atlas
Lung Adenocarcinoma dataset (N = 478, p < 0.0001).
Significantly, $\beta$-glucan worked synergistically with
IFN-$\gamma$ to reverse the risk signature by repolarizing the
MPE-M$\varphi$ toward the M1 pattern, enhancing anti-cancer
activity. CONCLUSIONS: We identified MPE-M$\varphi$ on the M1/M2
spectrum and plasticity and described a two-gene M1/M2 signature
that could predict the outcome of late-stage lung cancer
patients. In addition, we found that ``re-education'' of these
MPE-M$\varphi$ toward anti-cancer M1 macrophages using
clinically applicable strategies may overcome tumor immune
escape and benefit anti-cancer therapies.",
journal = "Cancer Immunol. Immunother.",
publisher = "Springer Science and Business Media LLC",
volume = 70,
number = 5,
pages = "1435--1450",
month = may,
year = 2021,
keywords = "Lung cancer; Macrophages; Malignant pleural effusion",
copyright = "https://creativecommons.org/licenses/by/4.0",
language = "en"
}
@ARTICLE{Karnevi2014-uc,
title = "Tumour-educated macrophages display a mixed polarisation and
enhance pancreatic cancer cell invasion",
author = "Karnevi, Emelie and Andersson, Roland and Rosendahl, Ann H",
abstract = "At the time of diagnosis, almost 80\% of pancreatic cancer
patients present with new-onset type 2 diabetes (T2D) or
impaired glucose tolerance. T2D and pancreatic cancer are both
associated with low-grade inflammation. Tumour-associated
macrophages (TAMs) have a key role in cancer-related
inflammation, immune escape, matrix remodelling and metastasis.
In this study, the interplay between tumour cells and immune
cells under the influence of different glucose levels was
investigated. Human peripheral blood mononuclear cells were
exposed in vitro to conditioned medium from BxPC-3 human
pancreatic cancer cells, in normal (5 mM) or high (25 mM)
glucose levels. Flow cytometry analyses demonstrated that
tumour-derived factors stimulated differentiation of
macrophages, with a mixed classical (M1-like) and alternatively
activated (M2-like) phenotype polarisation (CD11c(+)CD206(+)).
High-glucose conditions further enhanced the tumour-driven
macrophage enrichment and associated interleukin (IL)-6 and IL-8
cytokine levels. In addition, hyperglycaemia enhanced the
responsiveness of tumour-educated macrophages to
lipopolysaccharide, with elevated cytokine secretion compared
with normal glucose levels. Tumour-educated macrophages were
found to promote pancreatic cancer cell invasion in vitro, which
was significantly enhanced at high glucose. The anti-diabetic
drug metformin shifted the macrophage phenotype polarisation and
reduced the tumour cell invasion at normal, but not high,
glucose levels. In conclusion, this study demonstrates that
pancreatic cancer cells stimulate differentiation of macrophages
with pro-tumour properties that are further enhanced by
hyperglycaemia. These findings highlight important crosstalk
between tumour cells and TAMs in the local tumour
microenvironment that may contribute to disease progression in
pancreatic cancer patients with hyperglycaemia and T2D.",
journal = "Immunol. Cell Biol.",
publisher = "Wiley",
volume = 92,
number = 6,
pages = "543--552",
month = jul,
year = 2014,
copyright = "http://onlinelibrary.wiley.com/termsAndConditions#vor",
language = "en"
}
