Matteo Riva1,2, Roxanne Wouters1, Edmond Sterpin3, Roberto Giovannoni4, Louis Boon5, Uwe Himmelreich6, Willy Gsell6, Marc Van Ranst7, An Coosemans1,8. 1. Department of Oncology, Laboratory of Tumor Immunology and Immunotherapy, KU Leuven, Leuven, Belgium. 2. Department of Neurosurgery, University Hospital of Godinne, UCL Namur, Yvoir, Belgium. 3. Department of Oncology, Laboratory of Experimental Radiotherapy, KU Leuven, Leuven, Belgium. 4. School of Medicine and Surgery, University of Milano Bicocca, Monza, Italy. 5. Polpharma Biologics, Utrecht, the Netherlands. 6. Department of Imaging and Pathology and Molecular Small Animal Imaging Center (MoSAIC), Biomedical MRI, KU Leuven, Leuven, Belgium. 7. Rega Institute for Medical Research, Laboratory for Clinical and Epidemiological Virology, KU Leuven, Leuven, Belgium. 8. Department of Gynaecology and Obstetrics, Leuven Cancer Institute, UZ Leuven, Leuven, Belgium.
Abstract
BACKGROUND: The lack of immune synergy with conventional chemoradiation could explain the failure of checkpoint inhibitors in current clinical trials for high-grade gliomas (HGGs). OBJECTIVE: To analyze the impact of radiotherapy (RT), Temozolomide (TMZ) and antiprogrammed cell death protein 1 (αPD1) (as single or combined treatments) on the immune microenvironment of experimental HGGs. METHODS: Mice harboring neurosphere /CT-2A HGGs received RT (4 Gy, single dose), TMZ (50 mg/kg, 4 doses) and αPD1 (100 μg, 3 doses) as monotherapies or combinations. The influence on survival, tumor volume, and tumor-infiltrating immune cells was analyzed. RESULTS: RT increased total T cells (P = .0159) and cluster of differentiation (CD)8+ T cells (P = .0078) compared to TMZ. Lymphocyte subpopulations resulting from TMZ or αPD1 treatment were comparable with those of controls. RT reduced M2 tumor-associated macrophages/microglia (P = .0019) and monocytic myeloid derived suppressor cells (mMDSCs, P = .0003) compared to controls. The effect on mMDSC was also seen following TMZ and αPD1 treatment, although less pronounced (P = .0439 and P = .0538, respectively). Combining RT with TMZ reduced CD8+ T cells (P = .0145) compared to RT alone. Adding αPD1 partially mitigated this effect as shown by the increased CD8+ T cells/Tregs ratio, even if this result failed to reach statistical significance (P = .0973). Changing the combination sequence of RT, TMZ, and αPD1 did not alter survival nor the immune effects. CONCLUSION: RT, TMZ, and αPD1 modify the immune microenvironment of HGG. The combination of RT with TMZ induces a strong immune suppression which cannot be effectively counteracted by αPD1.
BACKGROUND: The lack of immune synergy with conventional chemoradiation could explain the failure of checkpoint inhibitors in current clinical trials for high-grade gliomas (HGGs). OBJECTIVE: To analyze the impact of radiotherapy (RT), Temozolomide (TMZ) and antiprogrammed cell death protein 1 (αPD1) (as single or combined treatments) on the immune microenvironment of experimental HGGs. METHODS:Mice harboring neurosphere /CT-2A HGGs received RT (4 Gy, single dose), TMZ (50 mg/kg, 4 doses) and αPD1 (100 μg, 3 doses) as monotherapies or combinations. The influence on survival, tumor volume, and tumor-infiltrating immune cells was analyzed. RESULTS: RT increased total T cells (P = .0159) and cluster of differentiation (CD)8+ T cells (P = .0078) compared to TMZ. Lymphocyte subpopulations resulting from TMZ or αPD1 treatment were comparable with those of controls. RT reduced M2 tumor-associated macrophages/microglia (P = .0019) and monocytic myeloid derived suppressor cells (mMDSCs, P = .0003) compared to controls. The effect on mMDSC was also seen following TMZ and αPD1 treatment, although less pronounced (P = .0439 and P = .0538, respectively). Combining RT with TMZ reduced CD8+ T cells (P = .0145) compared to RT alone. Adding αPD1 partially mitigated this effect as shown by the increased CD8+ T cells/Tregs ratio, even if this result failed to reach statistical significance (P = .0973). Changing the combination sequence of RT, TMZ, and αPD1 did not alter survival nor the immune effects. CONCLUSION: RT, TMZ, and αPD1 modify the immune microenvironment of HGG. The combination of RT with TMZ induces a strong immune suppression which cannot be effectively counteracted by αPD1.
Authors: Maxim O Politko; Alexandra Y Tsidulko; Oxana A Pashkovskaya; Konstantin E Kuper; Anastasia V Suhovskih; Galina M Kazanskaya; Lyubov S Klyushova; Dmitry K Sokolov; Alexander M Volkov; Evgenii E Kliver; Alexander A Zheravin; Svetlana V Aidagulova; Elvira V Grigorieva Journal: Int J Mol Sci Date: 2021-12-12 Impact factor: 5.923