Dexamethasone differentially depletes tumour and peripheral blood lymphocytes and can impact the efficacy of chemotherapy/checkpoint blockade combination treatment

Abstract

Dexamethasone is a synthetic glucocorticoid commonly used for the prevention and management of side effects in cancer patients undergoing chemotherapy. While it is effective as an anti-emetic and in preventing hypersensitivity reactions, dexamethasone depletes peripheral blood lymphocytes and impacts immune responses. The effect of dexamethasone on the number and quality of tumour-infiltrating leukocytes has not been reported. To address this, we calibrated the dose in two different strains of mice to achieve the same extent of peripheral blood lymphocyte depletion observed in patients with cancer. Doses that caused analogous depletion of T and B lymphocytes and NK cells from the peripheral blood, elicited no change in these populations within the tumour. The expression of immune checkpoint molecules PD-1, OX40, GITR and TIM3 on tumour-infiltrating lymphocytes was not altered. We found that dexamethasone had a small but significant deleterious impact on weakly efficacious chemoimmunotherapy but had no effect when the protocol was highly efficacious. Based on these results, we predict that dexamethasone will have a modest negative influence on the overall effectiveness of chemoimmunotherapy treatment.

Keywords: Dexamethasone; cancer; chemotherapy; immunotherapy; supportive care.

© 2019 The Author(s). Published with license by Taylor & Francis Group, LLC.

Figures

Figure 1.

Dexamethasone induces peripheral blood lymphodepletion in BALB/c and C57BL/6 mice similar to patients. (a), Treatment schedules for mesothelioma patients and (b), mice receiving dexamethasone. (c), Absolute CD3+ T lymphocyte numbers in peripheral blood of patients before and after dexamethasone administration. (d), Percentage change from baseline of lymphocytes in BALB/c and (e), C57BL/6J mice at different dosages of dexamethasone as measured on the Hemavet blood analyser. Depicted are mean percentages with SD, n = 6 for all groups; *p < .05, **p < .01, ***p < .001,****p < .0001 (comparison with PBS).

Figure 2.

Dexamethasone causes lymphodepletion in blood, but not in tumours. Blood and tumour samples were collected from mice that received either saline, 1.25 mg/kg or 5 mg/kg dexamethasone and analysed via flow cytometry. Percentage changes of (a), lymphoid and (b), myeloid immune subsets in blood and tumour from BALB/cArc mice treated with saline, 1.25 mg/kg dexamethasone or 5 mg/kg dexamethasone. (c), Analysis of activation marker ICOS and (d), proliferation marker Ki67 expression of CD4+ and CD8+ T lymphocytes and Tregs in blood and tumour. Depicted are mean percentages with SEM, n=8 for all groups; *p < .05, **p < .01, ***p < .001 (comparison with saline controls).

Figure 3.

Checkpoint molecule expression on tumour-infiltrating lymphocytes is not affected by dexamethasone. Flow cytometry analysis of tumour samples after dexamethasone treatment showing expression of immune checkpoint molecules GITR, OX40, PD-1 and TIM-3 on tumour-infiltrating T cells. (a), Foxp3−/CD4+ T helper cells. (b), FoxP3+ Tregs. (c), and CD8+ cytotoxic T cells. Depicted are mean percentages with SEM of the parent population. n = 5 for all groups; *p < .05, **p < .01.

Figure 4.

Dexamethasone has a differential effect on the in vivo therapeutic response of chemotherapy/checkpoint blockade combination therapy. Survival plot of s.c. AE17 mesothelioma-bearing C57BL/6 mice (a), n = 10 per group) or AB1 mesothelioma-bearing BALB/c mice (b), n = 15 per group) treated with cisplatin with or without anti-CTLA4/anti-PD-L1, with or without dexamethasone. (c), Survival plot of s.c. AB1 mesothelioma-bearing BALB/c mice treated with 5-FU with or without anti-CTLA4/anti-PD-L1, with or without dexamethasone (n = 10 per group). (d), Mean growth curves of AB1 tumours in BALB/c mice treated with anti-CTLA4/anti-PD-L1 checkpoint blockade (starting day 12) with or without 1.25 mg/kg dexamethasone (days 12–15). Log rank (Mantel-Cox) analysis performed on survival curves and a mixed model analysis of variance on tumour growth (n = 15 per group).