Background Increasing data indicate that corticosteroids can exert a detrimental effect on immunotherapy for oncology patients. Dexamethasone, a uniquely potent corticosteroid, is frequently administered to brain tumor patients to decrease tumor-associated edema, but limited data exist describing how dexamethasone affects the immune system systemically and intratumorally in glioblastoma patients – particularly in the context of immunotherapy.
Methods We evaluated the dose-dependent effects of dexamethasone when administered with PD-1 blockade and/or radiotherapy on survival and tumor response in immunocompetent C57BL/6 mice with syngeneic GL261 and CT-2A glioblastoma tumors. The immune microenvironment was comprehensively profiled using flow cytometry analysis. Clinically, the effect of dexamethasone on survival was evaluated in 181 IDH-wildtype glioblastoma patients treated with PD-(L)1 blockade, with adjustment for relevant prognostic factors using multivariable Cox regression.
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 (figure 1). Concurrent dexamethasone also abrogated survival following anti-PD-1 with or without radiotherapy in immunoresistant CT-2A models (figure 2). Dexamethasone decreased T lymphocyte numbers (figure 3) by increasing apoptosis (figure 4), in addition to decreasing lymphocyte functional capacity (figure 3C/D). Myeloid and NK cell populations were also generally reduced by dexamethasone (figure 3). Thus, dexamethasone appears to negatively affect both adaptive and innate immune responses. As a clinical correlate, a retrospective analysis of 181 consecutive IDH-wildtype glioblastoma patients treated with PD-(L)1 blockade revealed poorer survival among those on baseline dexamethasone. Upon multivariable adjustment by relevant prognostic factors, baseline dexamethasone administration was the strongest predictor of poor survival, regardless of dose (referent no dexamethasone; <2 mg HR 2.16, 95%CI: 1.30–3.68, p=0.003; ≥2 mg HR 1.97, 95%CI: 1.23–3.16, p=0.005; table 1 and figure 5).
Conclusions We demonstrate that concurrent dexamethasone administration, even at a low dose, limits the therapeutic benefit of anti-PD-1 therapy both in mouse glioblastoma models and in a retrospective cohort of 181 IDH-wildtype glioblastoma patients. Mechanistically, dexamethasone decreased intratumoral T cells and systemic levels of T cells, natural killer cells, and myeloid cells, while qualitatively impairing lymphocyte function. The mechanism of T cell depletion included induction of apoptosis. These findings indicate that dexamethasone hinders both adaptive and innate immune responses, intratumorally and systemically, and that its administration should be carefully assessed among glioblastoma patients undergoing second-generation immunotherapy clinical trials. Our findings also have ramifications for brain metastasis patients where immune checkpoint inhibitors are part of standard-of-care management.
Acknowledgements We thank Min Wu for assistance in generating CT-2A luciferase-transduced cells, and Drs. Geoffrey Young, Lei Qin, Xin Chen, and Jing Li for assistance in evaluation of patients‘ radiographic imaging.
Ethics Approval Approved under DFCI Institutional Review Board protocol 10-417.
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