Contrasting impact of corticosteroids on anti-PD-1 immunotherapy efficacy for tumor histologies located within or outside the central nervous system.
Immune checkpoint blockade targeting programmed cell death protein 1 (PD-1) is emerging as an important treatment strategy in a growing list of cancers, yet its clinical benefits are limited to a subset of patients. Further investigation of tumor-intrinsic predictors of response and how extrinsic factors, such as iatrogenic immunosuppression caused by conventional therapies, impact the efficacy of anti-PD-1 therapy are paramount. Given the widespread use of corticosteroids in cancer management and their immunosuppressive nature, this study sought to determine how corticosteroids influence anti-PD-1 responses and whether their effects were dependent on tumor location within the periphery versus central nervous system (CNS), which may have a more limiting immune environment. In well-established anti-PD-1-responsive murine tumor models, corticosteroid therapy resulted in systemic immune effects, including severe and persistent reductions in peripheral CD4+ and CD8 + T cells. Corticosteroid treatment was found to diminish the efficacy of anti-PD-1 therapy in mice bearing peripheral tumors with responses correlating with peripheral CD8/Treg ratio changes. In contrast, in mice bearing intracranial tumors, corticosteroids did not abrogate the benefits conferred by anti-PD-1 therapy. Despite systemic immune changes, anti-PD-1-mediated antitumor immune responses remained intact during corticosteroid treatment in mice bearing intracranial tumors. These findings suggest that anti-PD-1 responses may be differentially impacted by concomitant corticosteroid use depending on tumor location within or outside the CNS. As an immune-specialized site, the CNS may potentially play a protective role against the immunosuppressive effects of corticosteroids, thus sustaining antitumor immune responses mediated by PD-1 blockade.
['Maxwell|Russell|R|', 'Luksik|Andrew S|AS|', 'Garzon-Muvdi|Tomas|T|', 'Hung|Alice L|AL|', 'Kim|Eileen S|ES|0000-0002-5469-4058', 'Wu|Adela|A|', 'Xia|Yuanxuan|Y|0000-0001-6152-8392', 'Belcaid|Zineb|Z|', 'Gorelick|Noah|N|', 'Choi|John|J|0000-0002-5162-5903', 'Theodros|Debebe|D|', 'Jackson|Christopher M|CM|', 'Mathios|Dimitrios|D|', 'Ye|Xiaobu|X|', 'Tran|Phuoc T|PT|', 'Redmond|Kristin J|KJ|', 'Brem|Henry|H|', 'Pardoll|Drew M|DM|', 'Kleinberg|Lawrence R|LR|', 'Lim|Michael|M|']
corticosteroid immunotherapy central nervous system PD-1 brain tumor colon adenocarcinoma dexamethasone glioma