Abstract
The lack of immune synergy with conventional chemoradiation could explain the failure of checkpoint inhibitors in current clinical trials for high-grade gliomas (HGGs). 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. Mice harboring neurosphere /CT-2A HGGs received RT (4Gy, single dose), TMZ (50mg/kg, 4 doses) and αPD1 (100μg, 3 doses) as monotherapies or combinations. The influence on survival, tumor volume, and tumor-infiltrating immune cells was analyzed. 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. 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.
Highlights
Given the poor efficacy of current standard of care treatment, high-grade gliomas (HGGs) still represent an unmet clinical need.[1,2] Immunotherapy provided positive results in preclinical studies; clinical trials have failed to replicate such results in patients.[3–8] Importantly, only few animal studies assessed the combinatory effects of conventional and immune therapies; empirical combination schedules have been used for patients.[9]
We aimed at filling this knowledge gap by assessing the impact of radiotherapy (RT), Temozolomide (TMZ) and antiprogrammed cell death protein 1 treatment on the local immune microenvironment of experimental HGG
MMDSCs were approximately 40-times more abundant than 121 gMDSC. 122 123 Response to monotherapies is related to the immune profile
Summary
Given the poor efficacy of current standard of care treatment, high-grade gliomas (HGGs) still represent an unmet clinical need.[1,2] Immunotherapy provided positive results in preclinical studies; clinical trials have failed to replicate such results in patients.[3–8] Importantly, only few animal studies assessed the combinatory effects of conventional and immune therapies; empirical combination schedules have been used for patients.[9]. Only few animal studies assessed the combinatory effects of conventional and immune therapies; empirical combination schedules have been used for patients.[9]. Since conventional and immune therapies can heterogeneously modulate the tumor-immune microenvironment, these treatments could have been administered to HGG patients in non/low-synergistic combinations possibly reducing the efficacy of immunotherapy itself.[10–15]. We aimed at filling this knowledge gap by assessing the impact of radiotherapy (RT), Temozolomide (TMZ) and antiprogrammed cell death protein 1 treatment (αPD1) on the local immune microenvironment of experimental HGG. To analyze the impact of radiotherapy (RT), Temozolomide (TMZ) and anti-programmed cell 5 death protein 1 (αPD1) (as single or combined treatments) on the immune microenvironment of 6 experimental HGGs. 7 Methods. 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=0.0973). The combination of RT with TMZ induces a strong immune suppression which cannot be effectively counteracted by αPD1
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