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

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-gamma and TNF-alpha) 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.