Contrasting impact of corticosteroids on anti-PD-1 immunotherapy efficacy for tumor histologies located within or outside the central nervous system

Russell Maxwell, Andrew S. Luksik, Tomas Garzon-Muvdi, Alice L. Hung, Eileen S. Kim, Adela Wu, Yuanxuan Xia, Zineb Belcaid, Noah Gorelick, John Choi, Debebe Theodros, Christopher M. Jackson, Dimitrios Mathios, Xiaobu Ye, Phuoc T. Tran, Kristin J. Redmond, Henry Brem, Drew M. Pardoll, Lawrence R. Kleinberg, Michael Lim

Research output: Contribution to journalArticle

11 Scopus citations

Abstract

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.

Original languageEnglish (US)
Article numbere1500108
JournalOncoImmunology
Volume7
Issue number12
DOIs
StatePublished - Dec 2 2018
Externally publishedYes

Keywords

  • brain tumor
  • central nervous system
  • colon adenocarcinoma
  • corticosteroid
  • dexamethasone
  • glioma
  • immunotherapy
  • PD-1

ASJC Scopus subject areas

  • Immunology and Allergy
  • Immunology
  • Oncology

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    Maxwell, R., Luksik, A. S., Garzon-Muvdi, T., Hung, A. L., Kim, E. S., Wu, A., Xia, Y., Belcaid, Z., Gorelick, N., Choi, J., Theodros, D., Jackson, C. M., Mathios, D., Ye, X., Tran, P. T., Redmond, K. J., Brem, H., Pardoll, D. M., Kleinberg, L. R., & Lim, M. (2018). Contrasting impact of corticosteroids on anti-PD-1 immunotherapy efficacy for tumor histologies located within or outside the central nervous system. OncoImmunology, 7(12), [e1500108]. https://doi.org/10.1080/2162402X.2018.1500108