Saint John's Cancer Institute, Providence Saint John's Health Center, Santa Monica, CA, United States.
Department of Medicine, Keck School of Medicine, University of Southern California, Los Angeles, CA, United States.
Front Immunol. 2024 Apr 24;15:1373497. doi: 10.3389/fimmu.2024.1373497. eCollection 2024.
Intraoperative radiation therapy (IORT) delivers a single accelerated radiation dose to the breast tumor bed during breast-conserving surgery (BCS). The synergistic biologic effects of simultaneous surgery and radiation remain unclear. This study explores the cellular and molecular changes induced by IORT in the tumor microenvironment and its impact on the immune response modulation.
Patients with hormone receptor (HR)-positive/HER2-negative, ductal carcinoma (DCIS), or early-stage invasive breast carcinoma undergoing BCS with margin re-excision were included. Histopathological evaluation and RNA-sequencing in the re-excision tissue were compared between patients with IORT (n=11) vs. non-IORT (n=11).
Squamous metaplasia with atypia was exclusively identified in IORT specimens (63.6%, =0.004), mimicking DCIS. We then identified 1,662 differentially expressed genes (875 upregulated and 787 downregulated) between IORT and non-IORT samples. Gene ontology analyses showed that IORT was associated with the enrichment of several immune response pathways, such as inflammatory response, granulocyte activation, and T-cell activation (<0.001). When only considering normal tissue from both cohorts, IORT was associated with intrinsic apoptotic signaling, response to gamma radiation, and positive regulation of programmed cell death (<0.001). Using the xCell algorithm, we inferred a higher abundance of γδ T-cells, dendritic cells, and monocytes in the IORT samples.
IORT induces histological changes, including squamous metaplasia with atypia, and elicits molecular alterations associated with immune response and intrinsic apoptotic pathways. The increased abundance of immune-related components in breast tissue exposed to IORT suggests a potential shift towards active immunogenicity, particularly immune-desert tumors like HR-positive/HER2-negative breast cancer.
术中放疗（IORT）在保乳手术（BCS）期间向乳房肿瘤床单次加速给予辐射剂量。同时进行手术和放疗的协同生物学效应尚不清楚。本研究探讨了 IORT 在肿瘤微环境中诱导的细胞和分子变化及其对免疫反应调节的影响。
纳入接受 BCS 并再次切除边缘的激素受体（HR）阳性/HER2 阴性、导管癌（DCIS）或早期浸润性乳腺癌患者。比较 IORT（n=11）与非 IORT（n=11）患者的再次切除组织的组织病理学评估和 RNA 测序结果。
仅在 IORT 标本中发现（63.6%，=0.004）具有异型性的鳞状化生，类似于 DCIS。然后，我们在 IORT 和非 IORT 样本之间鉴定出 1662 个差异表达基因（875 个上调和 787 个下调）。基因本体分析表明，IORT 与几个免疫反应途径的富集相关，如炎症反应、粒细胞激活和 T 细胞激活（<0.001）。当仅考虑两个队列的正常组织时，IORT 与内在凋亡信号、γ 辐射反应和程序性细胞死亡的正调节相关（<0.001）。使用 xCell 算法，我们推断 IORT 样本中 γδ T 细胞、树突状细胞和单核细胞的丰度更高。
IORT 可诱导组织学变化，包括具有异型性的鳞状化生，并引发与免疫反应和内在凋亡途径相关的分子改变。暴露于 IORT 的乳腺组织中免疫相关成分的丰度增加表明，特别是 HR 阳性/HER2 阴性乳腺癌等免疫荒漠肿瘤，可能向活跃的免疫原性转变。
