Program in Women's Oncology, Women and Infants Hospital, Providence, RI, USA.
Women and Infants Hospital, Department of Obstetrics and Gynecology, Program in Women's Oncology, Warren-Alpert Medical School of Brown University, 200 Chestnut Street, Room 208, Providence, RI, 02903, USA.
J Ovarian Res. 2024 Sep 28;17(1):192. doi: 10.1186/s13048-024-01516-y.
High grade serous ovarian cancer (HGSOC) is the most lethal gynecologic malignancy in which patients have still yet to respond meaningfully to clinically available immunotherapies. Hence, novel immune targets are urgently needed. Our past work has identified that mast cells are significantly upregulated at the mRNA level in HGSOC patient tumors following neoadjuvant chemotherapy (NACT) exposure. Therefore, in this current investigation we sought to characterize intratumoral mast cell phenotypic changes as a result of NACT exposure and determine how these adaptations are associated with patient clinical outcomes.
Hematologic immunohistochemistry was employed to determine mast cell levels in 36 matched pre- and post-NACT HGSOC patient tumors. Fluorescent Immunohistochemistry was utilized to identify Tryptase+(carboxypeptidase A3 (CPA3) + mast cells as well as histamine levels in 29 and 20, respectively, matched pre- and post-NACT HGSOC patient tumors. Finally, human immortalized mast cells, LUVA were stimulated with carboplatin and paclitaxel and genomic changes were analyzed by quantitative PCR.
Hematologic labeled intratumoral mast cells were significantly upregulated in the intraepithelial and stromal regions of the tumor, post-NACT. Lower levels of pre-NACT mast cells were significantly associated with an improved progression-free survival (PFS). Histamine, a marker of mast cell degranulation was similarly upregulated in post-NACT exposed tumors. Through the characterization of mast cell specific proteases Tryptase and CPA3, it was found that Tryptase+/ CPA3 + mast cells were significantly upregulated both in the intraepithelial and stromal compartments of the tumor, while Tryptase + cells were significantly upregulated in the stromal regions of the tumor. Lower post-NACT treated levels with Tryptase+/ CPA3 + cells were significantly associated with improved overall survival (OS) and PFS while higher Tryptase + mast cells were associated with improved OS. Finally, following chemotherapy exposure mast cell activating factors AREG and CCL2 were significantly upregulated while TGFB1, an inhibitor of mast cell activation was downregulated in LUVA cells.
Enhanced mast cell numbers, as well as activation and degranulation are a consequence of NACT exposure. Post-NACT mast cells displayed differing associations with survival outcomes that was dependent upon granule classification. Ultimately, mast cells represent a clinically relevant putative HGSOC immune target.
高级别浆液性卵巢癌（HGSOC）是最致命的妇科恶性肿瘤，患者对临床可用的免疫疗法仍未产生明显反应。因此，迫切需要新的免疫靶点。我们过去的工作已经发现，在新辅助化疗（NACT）暴露后，HGSOC 患者肿瘤中的肥大细胞在 mRNA 水平上显著上调。因此，在本研究中，我们试图描述 NACT 暴露后肿瘤内肥大细胞表型的变化，并确定这些适应与患者临床结局的关系。
采用血液学免疫组织化学方法检测 36 例匹配的 NACT 前后 HGSOC 患者肿瘤中的肥大细胞水平。荧光免疫组织化学法分别用于鉴定 29 例和 20 例匹配的 NACT 前后 HGSOC 患者肿瘤中的 Tryptase+（羧肽酶 A3（CPA3）+肥大细胞和组氨酸水平。最后，用卡铂和紫杉醇刺激人永生化肥大细胞 LUVA，并通过定量 PCR 分析基因组变化。
NACT 后，肿瘤上皮内和基质区域的血液学标记的肿瘤内肥大细胞显著上调。NACT 前较低水平的肥大细胞与无进展生存期（PFS）的改善显著相关。脱颗粒肥大细胞的标志物组氨酸在暴露于 NACT 的肿瘤中也上调。通过对肥大细胞特异性蛋白酶 Tryptase 和 CPA3 的特征描述，发现 Tryptase+/CPA3+肥大细胞在上皮内和肿瘤基质区域均显著上调，而 Tryptase+细胞在上皮内和肿瘤基质区域均显著上调。NACT 后较低的 Tryptase+/CPA3+细胞水平与总生存期（OS）和 PFS 的改善显著相关，而较高的 Tryptase+肥大细胞与 OS 的改善相关。最后，化疗暴露后，肥大细胞激活因子 AREG 和 CCL2 显著上调，而 TGFB1（一种肥大细胞激活抑制剂）在 LUVA 细胞中下调。
NACT 暴露后，肥大细胞数量增加，以及激活和脱颗粒是 NACT 暴露的结果。NACT 后肥大细胞与生存结局的相关性不同，这取决于颗粒分类。最终，肥大细胞代表了一个具有临床相关性的潜在 HGSOC 免疫靶点。
