Early B cell changes predict autoimmunity following combination immune checkpoint blockade
Rituparna Das, Noffar Bar, Michelle Ferreira, Aaron M. Newman, Lin Zhang, Jithendra Kini Bailur, Antonella Bacchiocchi, Harriet Kluger, Wei Wei, Ruth Halaban, Mario Sznol, Madhav V. Dhodapkar, Kavita M. Dhodapkar
Rituparna Das, Noffar Bar, Michelle Ferreira, Aaron M. Newman, Lin Zhang, Jithendra Kini Bailur, Antonella Bacchiocchi, Harriet Kluger, Wei Wei, Ruth Halaban, Mario Sznol, Madhav V. Dhodapkar, Kavita M. Dhodapkar
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Concise Communication Immunology Oncology

Early B cell changes predict autoimmunity following combination immune checkpoint blockade

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.

Authors

Rituparna Das, Noffar Bar, Michelle Ferreira, Aaron M. Newman, Lin Zhang, Jithendra Kini Bailur, Antonella Bacchiocchi, Harriet Kluger, Wei Wei, Ruth Halaban, Mario Sznol, Madhav V. Dhodapkar, Kavita M. Dhodapkar

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Figure 3

Combination immune checkpoint therapy correlates with development of IRAEs.

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Combination immune checkpoint therapy correlates with development of IRA...
(A) Bulk PBMCs obtained from patients before and after 1 cycle of therapy with either anti-PD1 (n = 2), anti-CTLA4 (n = 5), or combination therapy with both anti-PD1 and anti-CTLA4 (n = 10) were examined for their BCR clonality. Graph shows B cell clonality (1/normalized Shannon index) in individual patients before and after therapy. Arrows indicate patients with increased B cell clonality (>1.5-fold) after therapy. (B) Correlation between changes in circulating B cells and days to onset of a grade 2 IRAE in patients receiving CCB therapy. Statistical data obtained via linear regression analysis (C) Change in circulating B cells after CCB therapy in patients who developed a grade 1 or 2 IRAE (n = 10) as well as in those who developed a grade 3 or 4 IRAE (n = 10). **P < 0.01, by 2-tailed Wilcoxon signed rank test.(D) Type and grade for IRAEs seen in patients receiving CCB therapy (n = 23). ITP, immune thrombocytopenia. (E) Kaplan-Meier plot showing the probability of survival without development of a grade 3 or higher IRAE in patients with (n = 8) or without (n = 15) B cell changes (decline in B cells <0.7, with a ≥2-fold increase in either CD21lo cells or plasmablasts after therapy). Statistical data obtained via Fisher’s exact test