Biology subjects

Meziani, L.

Publications and source records attributed to Meziani, L..

2 recordsLinked to original sources

bioRxiv2022

TGFβ receptor inhibition unleashes interferon-β production by tumor-associated macrophages and enhances radiotherapy efficacy

BackgroundTransforming growth factor-beta (TGF{beta}) can limit the efficacy of cancer treatments, including radiotherapy (RT), by inducing an immunosuppressive tumor environment. The association of TGF{beta} with impaired T cell infiltration and antitumor immunity is known, but the mechanisms by which TGF{beta} participates in immune cell exclusion and limits the efficacy of antitumor therapies warrant further investigations. MethodsWe used the clinically relevant TGF{beta} receptor 2 (TGF{beta}R2)-neutralizing antibody MT1 and the small molecule TGF{beta}R1 inhibitor LY3200882 and evaluated their efficacy in combination with RT against murine orthotopic models of head and neck and lung cancer. ResultsWe demonstrated that TGF{beta} pathway inhibition strongly increased the efficacy of RT. TGF{beta}R2 antibody upregulated interferon beta (IFN{beta}) expression in tumor-associated macrophages (TAMs) within the irradiated tumors and favored T cell infiltration at the periphery and within the core of the tumor lesions. We highlighted that both the antitumor efficacy and inhibition of immune exclusion observed with the combination of MT1 and RT were dependent on type I interferon signaling. ConclusionsThese data shed new light on the role of TGF{beta} in limiting the efficacy of RT, identifying a novel mechanism involving the inhibition of macrophage-derived type I interferon production, and fostering the use of TGF{beta}R inhibition in combination with RT in therapeutic strategies for the management of head and neck and lung cancer.

cancer biology↗

bioRxiv2020

Low doses of radiation therapy increase the immunosuppressive profile of lung macrophages via IL-10 production and IFNγ/IL-6 suppression: a therapeutic strategy to counteract lung inflammation?

Severe pneumonia and acute respiratory distress syndrome (ARDS) have been described in patients with severe COVID-19. Recently, early clinical data reported the efficacy of low doses of radiation therapy (RT) in the treatment of ARDS in patients with severe COVID-19. However, the involved mechanisms remained unknown. Here, we used airways-instilled lipopolysaccharide (LPS) and influenza virus (H1N1) as murine models of pneumonia, and Tolllike receptor (TLR)-3 stimulation in human lung macrophages. Low doses RT (0.5-1 Gy) decreased LPS induced pneumonia, and increased the percentage of Nerve- and Airway-associated Macrophages (NAMs) producing IL-10. During H1N1 viral infection, we observed decreased lung tissue damage and immune cell infiltration in irradiated animals. Low doses RT increased IL-10 production by infiltrating immune cells into the lung. Irradiation of TLR-3 ligand-stimulated human lung macrophages ex vivo increased IL-10 secretion and decreased IFN{gamma} production in the culture supernatant. The percentage of human lung macrophages producing IL-6 was also decreased. Our data highlight one of the mechanisms by which low doses RT regulate lung inflammation and skew lung macrophages towards an anti-inflammatory profile. These data provide the preclinical rationale for the use and for the optimization of low doses RT in situations such as COVID-19-induced ARDS.

immunology↗