CELL INTELLIGENCE · 肿瘤细胞治疗研究
肿瘤细胞治疗研究
英文原题：Myeloid cell networks govern re-establishment of original immune landscapes in recurrent ovarian cancer.
Myeloid cell networks govern re-establishment of original immune landscapes in recurrent ovarian cancer.
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免疫治疗在复发性卵巢癌（OC）中显示出有限的效果，其预后相关认识主要来自初治肿瘤。我们分析了来自五个独立队列的595例OC患者的697份肿瘤样本（566份原发性和131份复发性），刻画了TIL（肿瘤浸润淋巴细胞）（TILs）的异质性，并识别出四种与预后相关的免疫表型以及驱动恶性进展的TIL:髓系细胞网络。
我们发现，在模拟炎症型人类OC的临床前小鼠模型中，复发性Brca1 mut肿瘤维持了活化的TILs:树突状细胞（DCs）生态位，但通过上调COX/PGE 2信号逃避了免疫控制。相反，复发性Brca1 wt肿瘤表现为TILs:DCs生态位丢失，并积聚了免疫抑制性肿瘤微环境（TME）网络，其特征为Trem2/ApoE高表达的肿瘤相关巨噬细胞（TAMs）以及Nduf4l2高表达/Galectin3高表达的恶性状态。复发性肿瘤重现了原发肿瘤的免疫原性景观。
我们的研究结果揭示了BRCA依赖的TIL:髓系细胞交互作用是复发性OC持续免疫原性的关键，并提出增强化疗疗效的新靶点。
Immunotherapy has shown limited success in recurrent ovarian cancer (OC), with prognostic insights largely derived from treatment-naive tumors.
We analyzed 697 tumor samples (566 primary and 131 recurrent) from 595 OC patients across five independent cohorts, capturing tumor-infiltrating lymphocytes (TILs) heterogeneity and identifying four immune phenotypes linked to prognosis and TIL:myeloid networks driving malignant progression.
We found that in preclinical mouse models, mirroring inflamed human OCs, the recurrent Brca1 mut tumors maintained activated TILs:dendritic cells (DCs) niches but evaded immune control through upregulation of COX/PGE 2 signaling.
Conversely, recurrent Brca1 wt tumors displayed loss of TILs:DCs niches and accumulated immunosuppressive tumor microenvironment (TME) networks featuring Trem2/ApoE high tumor associated macrophages (TAMs) and Nduf4l2 high /Galectin3 high malignant states. Recurrent tumors recapitulate the immunogenic landscapes of original cancers.
Our findings reveal BRCA-dependent TIL:myeloid crosstalk as key to persistent immunogenicity in recurrent OC and propose new targets to enhance chemotherapy efficacy.
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