The glucocorticoids prednisone and dexamethasone differentially modulate T cell function in response to anti-PD-1 and anti-CTLA-4 immune checkpoint blockade

• Published in: Cancer Immunology, Immunotherapy Vol. 69; no. 8; pp. 1423 - 1436
• Main Authors: Okoye, Isobel S., Xu, Lai, Walker, John, Elahi, Shokrollah
• Format: Journal Article
• Language: English
• Published: Berlin/Heidelberg Springer Berlin Heidelberg 01.08.2020; Springer Nature B.V
• Subjects: Antibodies; Antibodies, Monoclonal - pharmacology; Antineoplastic Combined Chemotherapy Protocols - pharmacology; Cancer immunotherapy; Cancer Research; CD223 antigen; CTLA-4 Antigen - antagonists & inhibitors; CTLA-4 protein; Dexamethasone; Dexamethasone - administration & dosage; Effector cells; Glucocorticoids; Humans; Immune checkpoint inhibitors; Immunology; Immunotherapy; Inflammation; Interleukin 2; Jurkat Cells; Leukocytes (mononuclear); Leukocytes, Mononuclear - drug effects; Leukocytes, Mononuclear - immunology; Lymphocytes; Lymphocytes T; Medicine; Medicine & Public Health; Melanoma - drug therapy; Melanoma - immunology; Melanoma - metabolism; Melanoma - secondary; Metabolic response; Oncology; Original; Original Article; Patients; PD-1 protein; Peripheral blood mononuclear cells; Phosphorylation; Prednisone; Prednisone - administration & dosage; Prognosis; Programmed Cell Death 1 Receptor - antagonists & inhibitors; SHP-2 protein; Steroid hormones; Steroids; T-Lymphocytes - drug effects; T-Lymphocytes - immunology; Tumor necrosis factor-α; γ-Interferon; Prednisone; Dexamethasone; T cells; Immune check points
• ISSN: 0340-7004; 1432-0851
• DOI: 10.1007/s00262-020-02555-2

On-treatment steroids for countering immune checkpoint inhibitor-induced inflammatory responses (irAEs) are a hallmark of cancer immunotherapy. However, the suppressive nature of steroids has raised questions regarding their ability to compromise the function of the ‘proliferative burst’ of effector T cells induced by immune checkpoint antibodies. We investigated the effector functions and the co-inhibitory receptor profile of stimulated peripheral blood mononuclear cells (PBMCs) pre-treated with prednisone and dexamethasone alone or in the presence of anti-PD-1/CTLA-4 antibodies. Also, clinical analysis of a patient who exhibited irAEs following combination (anti-PD-1/CTLA-4) in the presence of glucocorticoids was done. We found that prednisone in contrast to dexamethasone did not compromise T cell cytokine production (IL-2, IFN-γ and TNF-α) and proliferation in the absence or presence of anti-PD-1/CTLA-4 antibodies, when a physiological concentration was used. Neither single prednisone treatment nor co-treatment with checkpoint inhibitors impacted the expression of co-inhibitory receptors PD-1, CTLA-4, TIM-3 and LAG-3. In contrast, dexamethasone treatment promoted downregulation of LAG-3 expression by T cells. In addition, co-treatment of PD-1 + Jurkat cells with prednisone and/or dexamethasone with anti-PD-1 before stimulation significantly reduced SHP-2 phosphorylation, indicative of increased T cell function. Our findings hereby demonstrate a differential steroid effect on T cell function, which should be taken into consideration for patients undergoing immunotherapy. Also, the clinical analysis of a patient who exhibited irAEs following combination (anti-PD-1/CTLA-4) therapy indicated complete metabolic response in the presence of glucocorticoids. Therefore, concomitant use of prednisone does not appear to interfere with the function of immune checkpoint blockade.