Proton irradiation orchestrates macrophage reprogramming through NFκB signaling

Genard, Géraldine; Wera, Anne Catherine; Huart, Camille; Calvé, Benjamin Le; Penninckx, Sébastien; Fattaccioli, Antoine; Tabarrant, Tijani; Demazy, Catherine; Ninane, Noëlle; Heuskin, Anne-Catherine; Lucas, Stéphane; Michiels, Carine

doi:10.1038/s41419-018-0757-9

Cited by 60 publications

(76 citation statements)

References 43 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…The NF-κB-pathway inhibitor (Bay11-7082; S2913, Selleckchem) or JNK inhibitor (SP600125; Sigma Aldrich) were added to the THP-1 macrophages at 10 μM or 30 μM 1 h or Immunofluorescence labeling. Immunofluorescence labeling was performed as described before 21,22 .…”

Section: Methodsmentioning

confidence: 99%

Cycling hypoxia promotes a pro-inflammatory phenotype in macrophages via JNK/p65 signaling pathway

Delprat

Tellier

Demazy

et al. 2020

Sci Rep

Self Cite

View full text Add to dashboard Cite

Cycling hypoxia (cyH), also called intermittent hypoxia, occurs in solid tumors and affects different cell types in the tumor microenvironment and in particular the tumor-associated macrophages (TAMs). As cyH and TAMs both favor tumor progression, we investigated whether cyH could drive the pro-tumoral phenotype of macrophages. Here, the effects of cyH on human THP-1 macrophages and murine bone marrow-derived macrophages (BMDM), either unpolarized M0, or polarized in M1 or M2 phenotype were studied. In M0 macrophages, cyH induced a pro-inflammatory phenotype characterized by an increase in tnfα and IL-8/MIP-2 secretion. CyH amplified the pro-inflammatory phenotype of M1 macrophages evidenced by an increased pro-inflammatory cytokine secretion and pro-inflammatory gene expression. Furthermore, cyH increased c-jun activation in human M0 macrophages and highly increased c-jun and NF-κB activation in M1 macrophages. C-jun and p65 are implicated in the effects of cyH on M0 and M1 macrophages since inhibition of their activation prevented the cyH pro-inflammatory effects. In conclusion, we demonstrated that cyH induces or amplifies a pro-inflammatory phenotype in M0 and M1 macrophages by activating JNK/p65 signaling pathway. These results highlight a specific role of cyH in the amplification of tumor-related inflammation by modulating the inflammatory phenotype of macrophages. Tumors are complex tissues composed of multiple cell types interacting and influencing each other, namely malignant cells and stromal cells like endothelial cells, immune cells and fibroblasts 1. The intricate combination of tumor microenvironment composition and environmental factors strongly determines tumor outcome 2. A major factor altering the tumor microenvironment is the presence of low oxygen tension called hypoxia, that is a common feature of malignant tumors 3. Two types of hypoxia can be distinguished: chronic and cycling hypoxia (cyH). Chronic hypoxia (chH) is associated to the limited oxygen distribution in a tissue; it is mainly the result of uncontrolled proliferation of O 2-consuming cancer cells and the O 2 diffusion gradient from blood capillaries 4,5. In contrast, cyH, also called intermittent hypoxia, is related to the irregular erythrocyte flux circulating in the anarchical tumor blood network characterized by the presence of temporary occlusions 6-8. The instability of blood flow leads to periods of hypoxia followed by periods of reoxygenation, occurring over hours through a clear pattern of periodicity 9. We previously demonstrated that cyH amplifies the endothelial inflammatory response induced by TNFα notably through an overactivation of NF-κB. Moreover, we showed that cyH enhances the overall tumor inflammation characterized by a global increase in inflammatory gene expression and by an increase in intratumor leukocyte infiltration in tumor-bearing mice 10. Inflammation is indeed described to be mutagenic and to favor proliferation and survival of malignant cells, angiogenesis, metastasis, corruption of the adaptive immu...

show abstract

Section: Methodsmentioning

confidence: 99%

Cycling hypoxia promotes a pro-inflammatory phenotype in macrophages via JNK/p65 signaling pathway

Delprat

Tellier

Demazy

et al. 2020

Sci Rep

Self Cite

View full text Add to dashboard Cite

show abstract

“…The inactivated M0 cells can be reprogrammed into polarized macrophages. These polarized cells can also be re‐educated to either M1 or M2 cells . M1 is a pro‐inflammatory phenotype with anti‐tumor activity, while M2 is an immunosuppressive cell type that contributes to tumor progression .…”

Section: Introductionmentioning

confidence: 99%

Macrophage polarity in cancer: A review

Najafi

Goradel

Farhood

et al. 2018

J of Cellular Biochemistry

401

313

View full text Add to dashboard Cite

Macrophages are the most abundant cells within the tumor stroma displaying noticeable plasticity, which allows them to perform several functions within the tumor microenvironment. Tumor-associated macrophages commonly refer to an alternative M2 phenotype, exhibiting anti-inflammatory and pro-tumoral effects. M2 cells are highly versatile and multi-tasking cells that directly influence multiple steps in tumor development, including cancer cell survival, proliferation, stemness, and invasiveness along with angiogenesis and immunosuppression. M2 cells perform these functions through critical interactions with cells related to tumor progression, including Th2 cells, cancer-associated fibroblasts, cancer cells, regulatory T cells (Tregs), and myeloid-derived suppressor cells. M2 cells also have negative cross-talks with tumor suppressor cells, including cytotoxic T cells and natural killer cells. Programed death-1 (PD-1) is one of the key receptors expressed in M2 cells that, upon interaction with its ligand PD-L1, plays cardinal roles for induction of immune evasion in cancer cells. In addition, M2 cells can neutralize the effects of the pro-inflammatory and anti-tumor M1 phenotype. Classically activated M1 cells express high levels of major histocompatibility complex molecules, and the cells are strong killers of cancer cells. Therefore, orchestrating M2 reprogramming toward an M1 phenotype would offer a promising approach for reversing the fate of tumor and promoting cancer regression. Macrophage switching toward an anti-inflammatory M1 phenotype could be used as an adjuvant with other approaches, including radiotherapy and immune checkpoint blockades, such as anti-PD-L1/PD-1 strategies.

show abstract

“…There is a great deal of evidence suggesting that an increased number of M2 macrophages is associated tumor growth, angiogenesis, invasion and metastasis (34,35). M2 cells promote tumor and local immunosuppression (36). Th2 cells release IL4 and IL13 and induce M2 cell polarization (37,38).…”

Section: Correlation Between Itga5 Expression Levels and Immune Markersmentioning

confidence: 99%

“…TAMs, derived from mononuclear cells, are induced to differentiate into M2 cells by cytokines such as IL-4, IL-10 and IL-13, which are secreted by Th2 cells(42). Moreover, M2 cells exhibit pro-tumoral activity by promoting genetic instability, angiogenesis, stem cell nurturing and local immunosuppression(36,43). Subsequently, IHC was performed on adjacent normal and tumor tissues extracted from gastric cancer patients to nd that Th2 cell markers such as STAT6, GATA3 and the M2 cell polarization marker CD163 were signi cantly increased in patients with high ITGA5 expression levels.…”

mentioning

confidence: 99%

ITGA5 Is a Prognostic Biomarker and Correlated with Immune Infiltration In Gastrointestinal Cancers

Zhu

Wang

Zhu

et al. 2020

Preprint

View full text Add to dashboard Cite

Background: Integrin Subunit Alpha 5 (ITGA5) belongs to the integrin alpha chain family, is vital for promoting cancer cell invasion, metastasis. However, the correlation between ITGA5 expression and immune infiltration in gastrointestinal (GI) tumors remain unclear.Methods: The expression levels of ITGA5 were detected by Oncomine and Tumor Immune Estimation Resource (TIMER). The association between ITGA5 and prognosis of patients was identified by Kaplan–Meier plotter, Gene Expression Profiling Interactive Analysis 2(GEPIA2) and PrognoScan. We evaluated the correlation between ITGA5 expression and immune infiltrating level via TIMER. Besides, TIMER and immunohistochemistry (IHC) staining were used to explore correlations between ITGA5 expression and markers of immune infiltrates cells. Furthermore, we constructed protein-protein interaction (PPI) network and performed functional enrichment by GeneMANIA and Metascape.Results: ITGA5 was generally overexpressed and correlated with worse prognosis in multiple types of GI tumors. In addition, ITGA5 expression levels was significantly associated with tumor purity and immune infiltration levels of different immune cells in GI tumors. Interestingly, Immune markers for monocytes, tumor - associated macrophages (TAMs), macrophages 2 (M2) cells and T-helper 2 (Th2) cells were found to be significantly and positively correlated with ITGA5 expression levels in colon and gastric cancer. Results from IHC staining further proved that markers of Th2 and M2 cell were significantly increased in gastric cancer patients with high ITGA5 expression levels. Lastly, interaction network and function enrichment analysis revealed ITGA5 were mainly involved in “integrin mediated signaling pathway”, “leukocyte migration”, “cell-substrate adhesion”.Conclutions: our study demonstrated that ITGA5 may act as an essential regulator of tumor immune cell infiltration and a valuable prognostic biomarker in GI tumors. Additional work is needed to fully elucidate the underlying mechanisms behind these observations.

show abstract

Proton irradiation orchestrates macrophage reprogramming through NFκB signaling

Cited by 60 publications

References 43 publications

Cycling hypoxia promotes a pro-inflammatory phenotype in macrophages via JNK/p65 signaling pathway

Cycling hypoxia promotes a pro-inflammatory phenotype in macrophages via JNK/p65 signaling pathway

Macrophage polarity in cancer: A review

ITGA5 Is a Prognostic Biomarker and Correlated with Immune Infiltration In Gastrointestinal Cancers

Contact Info

Product

Resources

About