Editors' ChoiceCancer

Later is better: Corticosteroids selectively suppress early memory T cells

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Science Translational Medicine  09 Oct 2019:
Vol. 11, Issue 513, eaaz3711
DOI: 10.1126/scitranslmed.aaz3711

Abstract

Systemic corticosteroid therapy selectively affects low-affinity memory CD8+ T cells and may alter the efficacy of immune checkpoint blockade.

Over the past ten years, immune checkpoint blockade (ICB) has shown marked effectiveness for treating a variety of advanced cancers. However, treatment with ICB is often complicated by immune-related adverse events (irAEs), which can be life-threatening if untreated. Treating irAEs may require systemic immunosuppressive medications, such as corticosteroids, which risks suppressing the ICBs’ antitumor effects. However, recent clinical literature suggests that short courses of systemic corticosteroids may not have much impact on antitumor effects, although mechanistic studies have been sparse.

To address these questions, Tokunaga et al. examined the effects of corticosteroids on a mouse melanoma model treated with ICB targeting either cytotoxic T lymphocyte–associated antigen 4 (CTLA-4) or programmed death ligand 1 (PD-L1) at different time points. The authors determined that early, but not late, steroid administration could result in tumor regrowth, suggesting that early steroids inhibited memory CD8+ T cells, which have been associated with lasting antitumor response. Further investigation revealed that ICB enhanced high-affinity, neoantigen-specific CD8+ T cell responses. Administration of systemic corticosteroids did not affect these high-affinity responses but did decrease low-affinity memory T cell responses in a time-dependent manner.

The authors next examined whether corticosteroid administration affected treatment response in a cohort of patients with metastatic melanoma treated with ipilimumab. They did not find a significant difference in survival between those who received corticosteroids within 16 versus 7 weeks. However, further subset analysis revealed that patients with low mutation burden who were treated with early steroids had worse prognosis, whereas timing did not appear to matter for those with high mutational burden. Because ipilimumab monotherapy is no longer the standard for advanced melanoma, expanded human studies of currently used ICB regimens will be necessary.

This work highlights the importance of further understanding the mechanisms by which ICB promotes antitumor response and identifying alternative means of suppressing irAEs while still maintaining the ICB effect. An important caveat is that only female mice were used for all experiments and the genders of the human patients are unknown. Larger preclinical studies with both genders of mice, expanded treatment regimens including combinations of checkpoint inhibitors, and clinical studies with well-defined cohorts will be necessary to confirm these findings and to determine the optimal timing and dose of immunosuppressive medication to minimize irAEs while still maximizing antitumor response.

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