Department of Cancer Immunology and Virology, Dana-Farber Cancer Institute, Boston, MA 02215, USA.
Center for Cancer Research at Mass General Hospital, Boston, MA 02114, USA; Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA.
Cell. 2022 May 12;185(10):1694-1708.e19. doi: 10.1016/j.cell.2022.03.033. Epub 2022 Apr 20.
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 hypoxia-induced 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.
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，这凸显了需要了解耐药机制的重要性。我们发现，在原发性乳腺癌中，抵抗 T 细胞攻击的肿瘤细胞处于静止状态。静止期癌细胞（QCCs）与免疫浸润减少的细胞形成簇。它们还表现出更高的致瘤能力和更高的化疗耐药性和干性基因表达。我们采用单细胞 RNA 测序技术，结合精确的空间分辨率，对 QCC 生态位内外浸润细胞进行了分析。这项转录组分析揭示了缺氧诱导的程序，并在 QCC 簇内发现了更多耗竭的 T 细胞、肿瘤保护性成纤维细胞和功能失调的树突状细胞。这揭示了基于肿瘤内位置的浸润细胞的不同表型。因此，QCC 通过协调局部缺氧免疫抑制环境来构成免疫治疗耐药性的储库，从而阻断 T 细胞功能。消除 QCC 有望抵抗免疫治疗耐药性并预防 TNBC 疾病复发。
