Quiescent cancer cells resist T cell attack by forming an immunosuppressive niche
Quiescent cancer cells resist T cell attack by forming an immunosuppressive niche
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DOI：
10.1016/j.cell.2022.03.033
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发表时间：
2022-05-12
期刊：
影响因子：
64.5
通讯作者：
Agudo, Judith
中科院分区：
文献类型：
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作者：
Baldominos, Pilar;Barbera-Mourelle, Alex;Agudo, Judith
免疫疗法是三阴性乳腺癌（TNBC）的一种有前途的治疗方法，但患者会复发，这突出了了解耐药机制的必要性。我们发现，在原发性乳腺癌中，抵抗T细胞攻击的肿瘤细胞是静止的。静止癌细胞（QCC）形成具有减少的免疫浸润的簇。它们还显示出上级致瘤能力和较高的化疗抗性和干性基因表达。我们采用具有精确空间分辨率的单细胞RNA测序来分析QCC小生境内外的浸润细胞。这种转录组学分析揭示了低氧诱导的程序，并在QCC簇内鉴定出更多耗尽的T细胞、肿瘤保护性成纤维细胞和功能失调的树突状细胞。这揭示了基于其肿瘤内位置的浸润细胞中的差异表型。因此，QCC通过协调阻断T细胞功能的局部缺氧免疫抑制环境而构成免疫治疗抗性储库。消除QCC有望抵消免疫疗法抗性并预防TNBC中的疾病复发。
Immunotherapy is a promising treatment for triple-negative breast cancer (TNBC), but patients relapse, highlighting the need to understand the mechanisms of resistance. We discovered that in primary breast cancer, tumor cells that resist T cell attack are quiescent. Quiescent cancer cells (QCCs) form clusters with reduced immune infiltration. They also display superior tumorigenic capacity and higher expression of chemotherapy resistance and stemness genes. We adapted single-cell RNA-sequencing with precise spatial resolution to profile infiltrating cells inside and outside the QCC niche. This transcriptomic analysis revealed hypoxiainduced programs and identified more exhausted T cells, tumor-protective fibroblasts, and dysfunctional dendritic cells inside clusters of QCCs. This uncovered differential phenotypes in infiltrating cells based on their intra-tumor location. Thus, QCCs constitute immunotherapy-resistant reservoirs by orchestrating a local hypoxic immune-suppressive milieu that blocks T cell function. Eliminating QCCs holds the promise to counteract immunotherapy resistance and prevent disease recurrence in TNBC.