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Glioblastoma (GBM), the most common adult primary brain tumor, has an average survival of only 15–18 months. Recently, the combination of immune checkpoint blockers paired with radiotherapy has shown promise in preclinical murine GBM models. Human clinical trials have largely failed. One reason for this may be the discrepancy between radiation protocols utilized in preclinical models versus clinical practice. For translational relevance, defining correct and comparable radiation dosages and schedules to achieve optimal synergy with immunotherapeutic drugs, is essential. We used the GL261-based syngeneic mouse GBM model to compare the effects of two radiation regimens on tumor cell growth and survival. We assessed the in vivo effects of a single dose of 10 Gy (10Gyx1) or five consecutive doses of 2 Gy (2Gyx5) on the tumor immune microenvironment over time and compared their efficacy when combined with anti-PD-1 in vivo . Our data show that the 10Gyx1 regimen is more effective than 2Gyx5 at inhibiting tumor cell proliferation and growth in vitro and in vivo . Both regimens preserved the antigen-presenting ability of both dendritic cells and local microglia, but 10Gyx1 led to the highest lymphocyte infiltration. The combination of radiation with the checkpoint blocker anti-PD-1 was advantageous for both radiation regimens with animals treated with the 10Gyx1 regimen surviving the longest. Our study highlights how radiation regimen choices may impact the translation of preclinical findings, and in particular, the effects of radiation and immunotherapy in GBM. This work and literature data on the effects of positive hypofractionation in human GBM patients suggest that applying fewer, higher-dose radiation fractions may benefit GBM patients and lead to tumoricidal effects without sacrificing favorable anti-tumor immune responders.

Natural regulatory T cells (nTregs) ensure the control of self-tolerance and are currently used in clinical trials to alleviate autoimmune diseases and graft-versus-host disease after hematopoietic stem cell transfer. Based on CD39/CD26 markers, blood nTreg analysis revealed the presence of five different cell subsets, each representing a distinct stage of maturation. Ex vivo added microenvironmental factors, including IL-2, TGFβ, and PGE2, direct the conversion from naive precursor to immature memory and finally from immature to mature memory cells, the latest being a no-return stage. Phenotypic and genetic characteristics of the subsets illustrate the structural parental maturation between subsets, which further correlates with the expression of regulatory factors. Regarding nTreg functional plasticity, both maturation stage and microenvironmental cytokines condition nTreg activities, which include blockade of autoreactive immune cells by cell-cell contact, Th17 and IL-10 Tr1-like activities, or activation of TCR-stimulating dendritic cell tolerization. Importantly, blood nTreg CD39/CD26 profile remained constant over a 2-y period in healthy persons but varied from person to person. Preliminary data on patients with autoimmune diseases or acute myelogenous leukemia illustrate the potential use of the nTreg CD39/CD26 profile as a blood biomarker to monitor chronic inflammatory diseases. Finally, we confirmed that naive conventional CD4 T cells, TCR-stimulated under a tolerogenic conditioned medium, could be ex vivo reprogrammed to FOXP3 lineage Tregs, and further found that these cells were exclusively committed to suppressive function under all microenvironmental contexts.