☆ 4.6 Article

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

NEUROSURGERY (2021)

Journal

NEUROSURGERY

Volume 88, Issue 2, Pages E205-E215

Publisher

LIPPINCOTT WILLIAMS & WILKINS

DOI: 10.1093/neuros/nyaa421

Keywords

High-grade glioma; Glioblastoma; Combination therapies; Immunotherapy; PD1; Temozolomide; Stereotactic radiotherapy

Funding

Fonds Wetenschappelijk Onderzoek (FWO) [1527719N]

Ask authors/readers for more resources

Protocol

Community support

Reagent

Community support

Automated Summary New
Abstract

The combination of RT with TMZ induces strong immune suppression in high-grade gliomas, which cannot be effectively counteracted by alpha PD1.

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 (alpha PD1) (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 alpha PD1 (100 mu g, 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 alpha PD1 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 alpha PD1 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 alpha PD1 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 alpha PD1 did not alter survival nor the immune effects. CONCLUSION: RT, TMZ, and alpha PD1 modify the immune microenvironment of HGG. The combination of RT with TMZ induces a strong immune suppression which cannot be effectively counteracted by alpha PD1.

Authors

I am an author on this paper

Click your name to claim this paper and add it to your profile.

Reviews

Primary Rating

4.6

Not enough ratings

Secondary Ratings

Novelty

Significance

Scientific rigor

Rate this paper

Reirradiation for Recurrent Glioblastoma: What We Know and What We Do Not

Jonathan P. S. Knisely, Howard A. Fine

Summary: The Oncology Grand Rounds series aims to provide clinical context to original reports published in the Journal. It includes case presentations, discussions on diagnostic and management challenges, literature reviews, and suggested management approaches by the authors. The goal is to help readers apply key study findings, including those from the Journal of Clinical Oncology, to their own clinical practice.

JOURNAL OF CLINICAL ONCOLOGY (2023)