Eva Reijmen1, Sven De Mey2, Wout De Mey1, Thierry Gevaert2, Kirsten De Ridder1, Hanne Locy1, Sandrina Martens3, Emmy De Blay4, Luc Bouwens4, Pieterjan Debie5, Karine Breckpot1, Jacques De Grève3, Mark De Ridder2, Cleo Goyvaerts6. 1. Laboratory of Molecular and Cellular Therapy, Department of Biomedical Sciences, Vrije Universiteit Brussel, Brussels, Belgium. 2. Department of Radiotherapy, Oncologisch Centrum, UZ Brussel, Vrije Universiteit Brussels, Brussels, Belgium. 3. Laboratory of Medical and Molecular Oncology (LMMO) and Department of Medical Genetics, UZ Brussel, Brussels, Belgium. 4. Cell Differentiation Lab, Vrije Universiteit Brussel, Brussels, Belgium. 5. In Vivo Cellular and Molecular Imaging Laboratory, Vrije Universiteit Brussel, Brussels, Belgium. 6. Laboratory of Molecular and Cellular Therapy, Department of Biomedical Sciences, Vrije Universiteit Brussel, Brussels, Belgium. Electronic address: cleo.goyvaerts@vub.be.
Abstract
PURPOSE: The combination of standard-of-care radiation therapy (RT) with immunotherapy is moving to the mainstream of non-small cell lung cancer treatment. Multiple preclinical studies reported on the CD8+ T cell stimulating properties of RT, resulting in abscopal therapeutic effects. A literature search demonstrates that most preclinical lung cancer studies applied subcutaneous lung tumor models. Hence, in-depth immunologic evaluation of clinically relevant RT in orthotopic lung cancer models is lacking. METHODS AND MATERIALS: We studied the therapeutic and immunologic effects of low-dose fractionated RT on lungs from C57BL/6 mice, challenged 2 weeks before with firefly luciferase expressing Lewis lung carcinoma cells via the tail vein. Low-dose fractionation was represented by 4 consecutive daily fractions of image guided RT at 3.2 Gy. RESULTS: We showed reduced lung tumor growth upon irradiation using in vivo bioluminescence imaging and immunohistochemistry. Moreover, significant immunologic RT-induced changes were observed in irradiated lungs and in the periphery (spleen and blood). First, a significant decrease in the number of CD8+ T cells and trends toward more CD4+ and regulatory T cells were seen after RT in all evaluated tissues. Notably, only in the periphery did the remaining CD8+ T cells show a more activated phenotype. In addition, a significant expansion of neutrophils and monocytes was observed upon RT locally and systemically. Locally, RT increased the influx of tumor-associated macrophages and conventional type 2 dendritic cells, whereas the alveolar macrophages and conventional type 1 DCs dramatically decreased. Functionally, these antigen-presenting cells severely reduced their CD86 expression, suggesting a reduced capacity to induce potent immunity. CONCLUSIONS: Our results imply that low-dose fractionated RT of tumor-bearing lung tissue shifts the immune cell balance toward an immature myeloid cell dominating profile. These data argue for myeloid cell repolarizing strategies to enhance the abscopal effects in patients with non-small cell lung cancer treated with fractionated RT.
PURPOSE: The combination of standard-of-care radiation therapy (RT) with immunotherapy is moving to the mainstream of non-small cell lung cancer treatment. Multiple preclinical studies reported on the CD8+ T cell stimulating properties of RT, resulting in abscopal therapeutic effects. A literature search demonstrates that most preclinical lung cancer studies applied subcutaneous lung tumor models. Hence, in-depth immunologic evaluation of clinically relevant RT in orthotopic lung cancer models is lacking. METHODS AND MATERIALS: We studied the therapeutic and immunologic effects of low-dose fractionated RT on lungs from C57BL/6 mice, challenged 2 weeks before with firefly luciferase expressing Lewis lung carcinoma cells via the tail vein. Low-dose fractionation was represented by 4 consecutive daily fractions of image guided RT at 3.2 Gy. RESULTS: We showed reduced lung tumor growth upon irradiation using in vivo bioluminescence imaging and immunohistochemistry. Moreover, significant immunologic RT-induced changes were observed in irradiated lungs and in the periphery (spleen and blood). First, a significant decrease in the number of CD8+ T cells and trends toward more CD4+ and regulatory T cells were seen after RT in all evaluated tissues. Notably, only in the periphery did the remaining CD8+ T cells show a more activated phenotype. In addition, a significant expansion of neutrophils and monocytes was observed upon RT locally and systemically. Locally, RT increased the influx of tumor-associated macrophages and conventional type 2 dendritic cells, whereas the alveolar macrophages and conventional type 1 DCs dramatically decreased. Functionally, these antigen-presenting cells severely reduced their CD86 expression, suggesting a reduced capacity to induce potent immunity. CONCLUSIONS: Our results imply that low-dose fractionated RT of tumor-bearing lung tissue shifts the immune cell balance toward an immature myeloid cell dominating profile. These data argue for myeloid cell repolarizing strategies to enhance the abscopal effects in patients with non-small cell lung cancer treated with fractionated RT.
Authors: Eva Reijmen; Sven De Mey; Helena Van Damme; Kirsten De Ridder; Thierry Gevaert; Emmy De Blay; Luc Bouwens; Christine Collen; Lore Decoster; Marijke De Couck; Damya Laoui; Jacques De Grève; Mark De Ridder; Yori Gidron; Cleo Goyvaerts Journal: Front Immunol Date: 2021-12-01 Impact factor: 7.561
Authors: Kirsten De Ridder; Hanne Locy; Elisa Piccioni; Miren Ibarra Zuazo; Robin Maximilian Awad; Stefaan Verhulst; Mathias Van Bulck; Yannick De Vlaeminck; Quentin Lecocq; Eva Reijmen; Wout De Mey; Lien De Beck; Thomas Ertveldt; Isabel Pintelon; Jean-Pierre Timmermans; David Escors; Marleen Keyaerts; Karine Breckpot; Cleo Goyvaerts Journal: Front Immunol Date: 2022-04-14 Impact factor: 8.786