Early B cell changes predict autoimmunity following combination immune checkpoint blockade

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

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.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Aged
  • Autoimmunity*
  • B-Lymphocytes / cytology*
  • B-Lymphocytes / drug effects
  • CTLA-4 Antigen / antagonists & inhibitors*
  • CTLA-4 Antigen / metabolism
  • Female
  • Humans
  • Immune System
  • Immunotherapy
  • Kaplan-Meier Estimate
  • Leukocytes, Mononuclear / cytology
  • Male
  • Melanoma / blood
  • Melanoma / drug therapy*
  • Middle Aged
  • Phenotype
  • Programmed Cell Death 1 Receptor / antagonists & inhibitors*
  • Programmed Cell Death 1 Receptor / metabolism
  • Risk
  • Skin Neoplasms / blood
  • Skin Neoplasms / drug therapy

Substances

  • CTLA-4 Antigen
  • CTLA4 protein, human
  • PDCD1 protein, human
  • Programmed Cell Death 1 Receptor