Therapy-induced senescence (TIS) is a primary response to chemotherapy, contributing to untoward treatment outcomes such as evasion of immunosurveillance. Despite the established role of the complement system in the immune response to cancer, the role of complement in mediating the immune response against senescent tumor cells remains poorly understood. To explore this relationship, we exposed lung adenocarcinoma (A549), breast adenocarcinoma (MCF7) and pancreatic carcinoma (Panc-1) cell lines to sublethal doses of either etoposide or doxorubicin to trigger TIS. Identification of TIS was based on morphological changes, upregulation of the senescence-associated β-galactosidase, p21^Cip1 induction and lamin B1 downregulation. Using immunofluorescence microscopy, quantitative PCR, ELISA of conditioned media and in silico analysis, we investigated complement activation, complement protein expression, C3 levels in the conditioned media of senescent cells and secreted complement proteins as part of the senescence-associated secretory phenotype (SASP), respectively. In cell lines undergoing TIS, complement-related changes included (i) activation of the terminal pathway, evidenced by the deposition of C5b-9 on senescent cells; (ii) an increase in the expression of CD59 and complement factor H and (iii) in A549 cells, an elevation in the expression of C3 with its secretion into the medium. In addition, increased C3 expression was observed in breast cancer samples expressing TIS hallmarks following exposure to neoadjuvant chemotherapy. In conclusion, TIS led to the activation of complement, upregulation of complement regulatory proteins and increased C3 expression. Complement appears to play a role in shaping the cancer microenvironment upon senescence induction.

中文翻译：

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治疗诱导的衰老癌细胞表现出补体激活和补体调节蛋白表达增加

治疗诱导衰老（TIS）是化疗的主要反应，会导致不良的治疗结果，例如逃避免疫监视。尽管补体系统在癌症免疫反应中的作用已被证实，但补体在介导针对衰老肿瘤细胞的免疫反应中的作用仍然知之甚少。为了探索这种关系，我们将肺腺癌 (A549)、乳腺癌 (MCF7) 和胰腺癌 (Panc-1) 细胞系暴露于亚致死剂量的依托泊苷或多柔比星以触发 TIS。 TIS 的鉴定基于形态学变化、衰老相关 β-半乳糖苷酶的上调、p21 ^Cip1诱导和核纤层蛋白 B1 下调。使用免疫荧光显微镜、定量 PCR、条件培养基 ELISA 和计算机分析，我们研究了衰老细胞条件培养基中的补体激活、补体蛋白表达、C3 水平以及作为衰老相关分泌表型 (SASP) 一部分的分泌补体蛋白， 分别。在经历 TIS 的细胞系中，补体相关的变化包括 (i) 终端途径的激活，由衰老细胞上 C5b-9 的沉积证明； (ii) CD59 和补体因子 H 的表达增加，以及 (iii) A549 细胞中 C3 的表达及其分泌到培养基中的增加。此外，在接受新辅助化疗后，在表达 TIS 标志的乳腺癌样本中观察到 C3 表达增加。总之，TIS 导致补体激活、补体调节蛋白上调和 C3 表达增加。补体似乎在诱导衰老时塑造癌症微环境中发挥着作用。