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J Clin Invest. 2018 Feb 1;128(2):715-720. doi: 10.1172/JCI96798. Epub 2018 Jan 8.

Early B cell changes predict autoimmunity following combination immune checkpoint blockade.

Author information

1
Department of Medicine.
2
Department of Pediatrics, Yale University School of Medicine, New Haven, Connecticut, USA.
3
Institute for Stem Cell Biology and Regenerative Medicine, and.
4
Department of Biomedical Data Science, Stanford University, Stanford, California, USA.
5
Department of Dermatology.
6
Yale Center for Analytic Sciences.
7
Yale Cancer Center, and.
8
Department of Immunobiology, Yale University School of Medicine, New Haven, Connecticut, USA.

Abstract

Combination checkpoint blockade (CCB) targeting inhibitory CTLA4 and PD1 receptors holds promise for cancer therapy. Immune-related adverse events (IRAEs) remain a major obstacle for the optimal application of CCB in cancer. Here, we analyzed B cell changes in patients with melanoma following treatment with either anti-CTLA4 or anti-PD1, or in combination. CCB therapy led to changes in circulating B cells that were detectable after the first cycle of therapy and characterized by a decline in circulating B cells and an increase in CD21lo B cells and plasmablasts. PD1 expression was higher in the CD21lo B cells, and B cell receptor sequencing of these cells demonstrated greater clonality and a higher frequency of clones compared with CD21hi cells. CCB induced proliferation in the CD21lo compartment, and single-cell RNA sequencing identified B cell activation in cells with genomic profiles of CD21lo B cells in vivo. Increased clonality of circulating B cells following CCB occurred in some patients. Treatment-induced changes in B cells preceded and correlated with both the frequency and timing of IRAEs. Patients with early B cell changes experienced higher rates of grade 3 or higher IRAEs 6 months after CCB. Thus, early changes in B cells following CCB may identify patients who are at increased risk of IRAEs, and preemptive strategies targeting B cells may reduce toxicities in these patients.

KEYWORDS:

Cancer immunotherapy; Immunology; Oncology

PMID:
29309048
PMCID:
PMC5785243
DOI:
10.1172/JCI96798
[Indexed for MEDLINE]
Free PMC Article

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