Radiotherapy, Temozolomide, and Antiprogrammed Cell Death Protein 1 Treatments Modulate the Immune Microenvironment in Experimental High-Grade Glioma

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. Copyright © 2020 by the Congress of Neurological Surgeons