Department of Internal Medicine, Section of Medical Oncology, Yale University, New Haven, CT, USA.
Division of Hematology and Oncology, Department of Internal Medicine, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA.
Breast Cancer Res Treat. 2024 Nov;208(2):369-377. doi: 10.1007/s10549-024-07426-3. Epub 2024 Jul 13.
We evaluated T- and B-cell receptor (TCR and BCR) repertoire diversity and 38 serum cytokines in pre- and post-treatment peripheral blood of 66 patients with triple-negative breast cancer (TNBC) who received neoadjuvant chemotherapy plus durvalumab and assessed associations with pathologic response and immune-related adverse events (irAEs) during treatment.
Genomic DNA was isolated from buffy coat for TCR and BCR clonotype profiling using the Immunoseq platform and diversity was quantified with Pielou's evenness index. MILLIPLEX MAP Human Cytokine/Chemokine Magnetic Bead Panel was used to measure serum cytokine levels, which were compared between groups using moderated t-statistic with Benjamini-Hochberg correction for multiple testing.
TCR and BCR diversity was high (Pielou's index > 0.75) in all samples. Baseline receptor diversities and change in diversity pre- and post-treatment were not associated with pathologic response or irAE status, except for BCR diversity that was significantly lower post-treatment in patients who developed irAE (unadjusted p = 0.0321). Five cytokines increased after treatment in patients with pathologic complete response (pCR) but decreased in patients with RD, most prominently IL-8. IFNγ, IL-7, and GM-CSF levels were higher in pre-treatment than in post-treatment samples of patients who developed irAEs but were lower in those without irAEs.
Baseline peripheral blood cytokine levels may predict irAEs in patients treated with immune checkpoint inhibitors and chemotherapy, and increased post-treatment B-cell clonal expansion might mediate irAEs.
我们评估了 66 例接受新辅助化疗加 durvalumab 的三阴性乳腺癌（TNBC）患者治疗前后外周血中的 T 细胞和 B 细胞受体（TCR 和 BCR）库多样性和 38 种血清细胞因子，并评估了它们与病理缓解和治疗期间免疫相关不良事件（irAEs）的相关性。
从白细胞层分离基因组 DNA，使用 Immunoseq 平台进行 TCR 和 BCR 克隆型分析，并使用皮尔逊均匀度指数定量多样性。使用 MILLIPLEX MAP 人类细胞因子/趋化因子磁珠面板测量血清细胞因子水平，并使用带有 Benjamini-Hochberg 多重检验校正的调整 t 检验比较组间差异。
所有样本的 TCR 和 BCR 多样性均较高（皮尔逊指数>0.75）。基线受体多样性以及治疗前后的变化与病理缓解或 irAE 状态无关，但在发生 irAE 的患者中，治疗后 BCR 多样性显著降低（未调整的 p=0.0321）。在发生病理完全缓解（pCR）的患者中，有 5 种细胞因子在治疗后增加，但在缓解疾病的患者中减少，其中最明显的是 IL-8。IFNγ、IL-7 和 GM-CSF 的水平在发生 irAE 的患者的治疗前样本中高于治疗后样本，但在没有 irAE 的患者中则较低。
基线外周血细胞因子水平可能预测接受免疫检查点抑制剂和化疗治疗的患者的 irAE，并且治疗后 B 细胞克隆扩增增加可能介导 irAE。
