Concurrent Dexamethasone Limits the Clinical Benefit of Immune Checkpoint Blockade in Glioblastoma

Clin Cancer Res. 2021 Jan 1;27(1):276-287. doi: 10.1158/1078-0432.CCR-20-2291. Epub 2020 Nov 25.


Purpose: Dexamethasone, a uniquely potent corticosteroid, is frequently administered to patients with brain tumors to decrease tumor-associated edema, but limited data exist describing how dexamethasone affects the immune system systemically and intratumorally in patients with glioblastoma (GBM), particularly in the context of immunotherapy.

Experimental design: We evaluated the dose-dependent effects of dexamethasone when administered with programmed cell death 1 (PD-1) blockade and/or radiotherapy in immunocompetent C57BL/6 mice with syngeneic GL261 and CT-2A GBM tumors. Clinically, the effect of dexamethasone on survival was evaluated in 181 patients with isocitrate dehydrogenase (IDH) wild-type GBM treated with PD-(L)1 blockade, with adjustment for relevant prognostic factors.

Results: Despite the inherent responsiveness of GL261 to immune checkpoint blockade, concurrent dexamethasone administration with anti-PD-1 therapy reduced survival in a dose-dependent manner. Concurrent dexamethasone also abrogated survival following anti-PD-1 therapy with or without radiotherapy in immune-resistant CT-2A models. Dexamethasone decreased T-lymphocyte numbers by increasing apoptosis, in addition to decreasing lymphocyte functional capacity. Myeloid and natural killer cell populations were also generally reduced by dexamethasone. Thus, dexamethasone appears to negatively affect both adaptive and innate immune responses. As a clinical correlate, a retrospective analysis of 181 consecutive patients with IDH wild-type GBM treated with PD-(L)1 blockade revealed poorer survival among those on baseline dexamethasone. Upon multivariable adjustment with relevant prognostic factors, baseline dexamethasone administration was the strongest predictor of poor survival [reference, no dexamethasone; <2 mg HR, 2.16; 95% confidence interval (CI), 1.30-3.68; P = 0.003 and ≥2 mg HR, 1.97; 95% CI, 1.23-3.16; P = 0.005].

Conclusions: Our preclinical and clinical data indicate that concurrent dexamethasone therapy may be detrimental to immunotherapeutic approaches for patients with GBM.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • B7-H1 Antigen / antagonists & inhibitors
  • Brain Edema / drug therapy*
  • Brain Edema / etiology
  • Brain Neoplasms / complications
  • Brain Neoplasms / genetics
  • Brain Neoplasms / mortality
  • Brain Neoplasms / therapy*
  • Cell Line, Tumor / transplantation
  • Chemoradiotherapy / methods
  • Dexamethasone / pharmacology*
  • Dexamethasone / therapeutic use
  • Disease Models, Animal
  • Dose-Response Relationship, Drug
  • Drug Interactions
  • Female
  • Follow-Up Studies
  • Glioblastoma / complications
  • Glioblastoma / genetics
  • Glioblastoma / mortality
  • Glioblastoma / therapy*
  • Humans
  • Immune Checkpoint Inhibitors / pharmacology*
  • Immune Checkpoint Inhibitors / therapeutic use
  • Isocitrate Dehydrogenase / genetics
  • Kaplan-Meier Estimate
  • Mice
  • Prognosis
  • Programmed Cell Death 1 Receptor / antagonists & inhibitors
  • Retrospective Studies
  • Tumor Microenvironment / drug effects
  • Tumor Microenvironment / immunology


  • B7-H1 Antigen
  • CD274 protein, human
  • Immune Checkpoint Inhibitors
  • Pdcd1 protein, mouse
  • Programmed Cell Death 1 Receptor
  • Dexamethasone
  • Isocitrate Dehydrogenase