Department of Obstetrics and Gynecology, Würzburg University Hospital, University of Würzburg, Würzburg, Germany.
Interdisciplinary Center for Clinical Research (IZKF), Würzburg University Hospital, University of Würzburg, Würzburg, Germany.
Cancer Res. 2019 Apr 1;79(7):1507-1519. doi: 10.1158/0008-5472.CAN-18-0387. Epub 2019 Jan 28.
Targeting of tumor immune escape mechanisms holds enormous therapeutic potential. Still, most patients progress under immune checkpoint blockade and some even become hyperprogressors. To investigate how cancer cells respond to activated but ineffective T cells, we challenged peptide-loaded MCF-7 breast cancer cells with antigen-specific CD8 T cells in which lytic granules had been destroyed by pretreatment with Concanamycin A. Gene expression analysis after coculture revealed simultaneous induction of PD-L1, IDO1, CEACAM1, and further immunoregulatory checkpoints in breast cancer cells. Strikingly, we further observed gene signatures characteristic for dedifferentiation and acquisition of pluripotency markers including Yamanaka factors. Cognate interaction with nonlytic CD8 T cells also increased the proportion of stem cell-like cancer cells in a cell-to-cell contact- or (at least) proximity-dependent manner in various cell lines and in primary breast cancer cell cultures; this induction of stem cell-like properties was confirmed by enhanced tumor-forming capacity in immunodeficient mice. Resulting tumors were characterized by enhanced cell density, higher proliferation rates, and increased propensity for lymphoid metastasis. These findings describe a widely underappreciated pathway for immune escape, namely immune-mediated dedifferentiation of breast cancer cells, which is associated with profound changes in gene expression and cellular behavior. As the enhanced malignant potential of cancer cells after nonlytic cognate interactions with CD8 T cells enables increased tumor growth and metastasis in BALB/c mice, the described mechanism may provide a possible explanation for the clinical phenomenon of hyperprogression in response to unsuccessful immunotherapy. SIGNIFICANCE: This study shows that ineffective immune responses not only fail to clear a malignancy, but can also activate pathways in cancer cells that promote stemness and tumor-seeding capacity.
靶向肿瘤免疫逃逸机制具有巨大的治疗潜力。尽管如此，大多数患者在免疫检查点阻断下仍会进展，有些甚至成为超进展者。为了研究癌细胞如何对激活但无效的 T 细胞作出反应，我们用抗原特异性 CD8 T 细胞挑战负载肽的 MCF-7 乳腺癌细胞，这些 T 细胞的裂解颗粒已被康纳霉素 A 预处理破坏。共培养后的基因表达分析显示，乳腺癌细胞同时诱导了 PD-L1、IDO1、CEACAM1 和其他免疫调节检查点。引人注目的是，我们还观察到了具有去分化特征的基因特征，并获得了多能性标志物，包括 Yamanaka 因子。与非裂解性 CD8 T 细胞的同源相互作用也以细胞间接触或（至少）接近依赖性方式增加了各种细胞系和原代乳腺癌细胞培养物中类干细胞样癌细胞的比例；这种诱导类干细胞样特性通过在免疫缺陷小鼠中增强肿瘤形成能力得到了证实。由此产生的肿瘤的特征是细胞密度增加、增殖率提高和淋巴转移倾向增加。这些发现描述了一种广泛被低估的免疫逃逸途径，即免疫介导的乳腺癌细胞去分化，这与基因表达和细胞行为的深刻变化有关。由于与 CD8 T 细胞的非裂解性同源相互作用增强了癌细胞的恶性潜能，使 BALB/c 小鼠中的肿瘤生长和转移增加，因此所描述的机制可能为免疫治疗失败时出现的临床超进展现象提供了一种可能的解释。意义：本研究表明，无效的免疫反应不仅未能清除恶性肿瘤，还可以激活癌细胞中的促进干性和肿瘤播种能力的途径。
