Long-term Sculpting of the B-cell Repertoire following Cancer Immunotherapy in Patients Treated with Sipuleucel-T.
Long-term Sculpting of the B-cell Repertoire following Cancer Immunotherapy in Patients Treated with Sipuleucel-T.
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DOI：
10.1158/2326-6066.cir-20-0252
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发表时间：
2020-12
影响因子：
10.1
通讯作者：
Fong L
中科院分区：
文献类型：
--
作者：
Zhang L;Kandadi H;Yang H;Cham J;He T;Oh DY;Sheikh NA;Fong L
Sipuleucel-T是一种自体细胞免疫疗法，最多输注3次，用于转移性去势抵抗性前列腺癌（mCRPC）。Sipuleucel-T诱导T细胞和B细胞对前列腺酸性磷酸酶（PAP）的反应，与改善生存相关。sipuleucel-T对肿瘤抗原特异性免疫记忆的长期影响仍然未知。特别是，通过抗原特异性抗体应答和B细胞受体（BCR）序列测量的B细胞应答仍然未知。为了评估sipuleucel-T是否可以诱导长期免疫记忆，我们在两组mCRPC患者中检查了sipuleucel-T治疗前后的循环B细胞应答：既往接受过sipuleucel-T治疗的患者（治疗;中位数，自上次治疗以来的8.9年）与未接受过sipuleucel-T治疗的患者（初治）。在重新治疗之前，与初治患者相比，既往接受过治疗的患者表现出持续的抗体反应以及更集中和收敛的BCR谱系，具有不同的V（D）J基因使用。再次治疗后，既往接受过治疗的患者维持了高频率克隆，并在较早的时间点产生了更多的收敛性BCR，这与首次治疗的患者不同。特别是在第一次sipuleucel-T输注的情况下，先前接受过治疗的患者在100个最丰富的基线克隆中具有较少的改组。相反，初治患者表现出很大的BCR转换，新的B细胞克隆持续流入。社会网络分析表明，以前接受治疗的患者具有更高度组织化的B细胞库，与更高的克隆成熟一致。较高的治疗诱导的BCR克隆性与初治患者的较长生存期相关。这些结果证明了sipuleucel-T诱导长期免疫记忆和B细胞库持久变化的能力。
Sipuleucel-T is an autologous cellular immunotherapy, administered up to 3 infusions, for metastatic castration-resistant prostate cancer (mCRPC). Sipuleucel-T induces T- and B-cell responses to prostatic acid phosphatase (PAP), correlating to improved survival. The long-term impact of sipuleucel-T on tumor antigen-specific immunologic memory remains unknown. In particular, B cell responses, as measured by antigen-specific antibody responses and B cell receptor (BCR) sequences, remain unknown. To evaluate whether sipuleucel-T could induce long-term immunologic memory, we examined circulating B cell responses before and after sipuleucel-T treatment in two groups of mCRPC patients: those who had previously received sipuleucel-T (treated; median, 8.9 years since the previous treatment) versus those who had not (naïve). Before re-treatment, previously treated patients exhibited persistent antibody responses as well as more focused and convergent BCR repertoires with distinct V(D)J gene usage compared with naïve patients. After retreatment, previously treated patients maintained high frequency clones and developed more convergent BCRs at earlier time points unlike naive patients. With the first sipuleucel-T infusion specifically, previously-treated patients had less shuffling within the 100-most abundant baseline clones. In contrast, naïve patients exhibited great BCR turnover with a continued influx of new B cell clones. Social network analysis showed that previously treated patients had more highly organized B cell repertoires, consistent with greater clonal maturation. Higher treatment-induced BCR clonality correlated with longer survival for naïve patients. These results demonstrated the capacity of sipuleucel-T to induce long-term immune memory and lasting changes to the B cell repertoire.