Early B cell changes predict autoimmunity following combination immune checkpoint blockade

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 [CD21.sup.lo] B cells and plasmablasts. PD1 expression was higher in the [CD21.sup.lo] B cells, and B cell receptor sequencing of these cells demonstrated greater clonality and a higher frequency of clones compared with [CD21.sup.hi] cells. CCB induced proliferation in the [CD21.sup.lo] compartment, and single-cell RNA sequencing identified B cell activation in cells with genomic profiles of [CD21.sup.lo] 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.
Introduction Combination checkpoint blockade (CCB) therapy with anti-CTLA4 and anti-PD1 for the treatment of patients with melanoma leads to higher response rates and progression-free survival compared with treatment with either [...]