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^lo B cells and plasmablasts. PD1 expression was higher in the CD21^lo B cells, and B cell receptor sequencing of these cells demonstrated greater clonality and a higher frequency of clones compared with CD21^hi cells. CCB induced proliferation in the CD21^lo compartment, and single-cell RNA sequencing identified B cell activation in cells with genomic profiles of CD21^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.

中文翻译：

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联合免疫检查点封锁后，早期B细胞变化可预测自身免疫

靶向抑制性CTLA4和PD1受体的联合检查站封锁（CCB）有望用于癌症治疗。免疫相关不良事件（IRAE）仍然是CCB在癌症中最佳应用的主要障碍。在这里，我们分析了用抗CTLA4或抗PD1或联合治疗后黑色素瘤患者的B细胞变化。CCB治疗导致循环B细胞变化，在治疗的第一个周期后即可检测到，其特征是循环B细胞减少，CD21 ^lo B细胞和成浆细胞增加。PD21在CD21 ^lo B细胞中的表达较高，与CD21 ^hi相比，这些细胞的B细胞受体测序显示出更高的克隆性和更高的克隆频率细胞。CCB诱导CD21 ^{lo B}区室增殖，单细胞RNA测序鉴定了体内具有CD21 ^lo B细胞基因组概况的细胞中的B细胞活化。在某些患者中，CCB后循环B细胞的克隆性增加。治疗诱导的B细胞变化在IRAE的频率和时机之前并与之相关。B细胞早期改变的患者在CCB后6个月经历了更高的3级或更高的IRAEs发生率。因此，CCB后B细胞的早期变化可能会识别出IRAE风险增加的患者，针对B细胞的抢先策略可能会降低这些患者的毒性。