Purpose: The immunological profile of early-stage breast cancer treated with neoadjuvant PARP inhibitors has not been described. The aim of this study was to delineate the changes in the tumor immune microenvironment (TiME) induced by talazoparib. Patients and Methods: Patients with operable germline BRCA1/2 pathogenic variant (gBRCA1/2+) breast cancer were enrolled in a feasibility study of neoadjuvant talazoparib. Thirteen patients who received 8 weeks of neoadjuvant talazoparib were available for analysis, including 11 paired pre- and post-talazoparib core biopsies. Treatment-related changes in tumor-infiltrating lymphocytes were examined and immune cell phenotypes and their spatial distribution in the TiME were identified and quantified by multiplex immunofluorescence using a panel of 6 biomarkers (CD3, CD8, CD68, PD-1, PD-L1, and CK). Results: Neoadjuvant talazoparib significantly increased infiltrating intratumoral and stromal T-cell and cytotoxic T-cell density. There was no difference in PD-1 or PD-L1 immune cell phenotypes in the pre- and post-talazoparib specimens and PD-L1 expression in tumor cells was rare in this cohort. Spatial analysis demonstrated that pre-talazoparib interactions between macrophages and T cells may correlate with pathologic complete response. Conclusions: This is the first study with phenotyping to characterize the immune response to neoadjuvant talazoparib in patients with gBRCA1/2+ breast cancer. These findings support an emerging role for PARP inhibitors in enhancing tumor immunogenicity. Further investigation of combinatorial strategies is warranted with agents that exploit the immunomodulatory effects of PARP inhibitors on the TiME.

中文翻译：

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Talazoparib 新辅助治疗具有遗传性 BRCA 突变的早期乳腺癌患者的初步研究中通过多重免疫荧光染色观察肿瘤免疫微环境的变化

目的：尚未描述用新辅助 PARP 抑制剂治疗的早期乳腺癌的免疫学特征。本研究的目的是描述他拉佐帕尼诱导的肿瘤免疫微环境（TiME）的变化。患者和方法：患有可手术种系 BRCA1/2 致病性变异 (gBRCA1/2+) 乳腺癌的患者被纳入新辅助他拉佐帕尼的可行性研究。接受 8 周新辅助 Talazoparib 治疗的 13 名患者可供分析，其中包括 11 例配对的 Talazoparib 前后核心活检组织。检查肿瘤浸润淋巴细胞中与治疗相关的变化，并使用 6 种生物标志物（CD3、CD8、CD68、PD-1、PD-L1、和CK）。结果：新辅助talazoparib显着增加浸润瘤内和间质T细胞以及细胞毒性T细胞密度。在他拉佐帕尼治疗前后样本中，PD-1 或​​ PD-L1 免疫细胞表型没有差异，并且该队列中肿瘤细胞中的 PD-L1 表达很少。空间分析表明，talazoparib 治疗前巨噬细胞和 T 细胞之间的相互作用可能与病理完全缓解相关。结论：这是第一项通过表型分析来表征 gBRCA1/2+ 乳腺癌患者对新辅助他拉佐帕尼免疫反应的研究。这些发现支持 PARP 抑制剂在增强肿瘤免疫原性方面的新兴作用。需要进一步研究利用 PARP 抑制剂对 TiME 免疫调节作用的药物的组合策略。