Lung Research Laboratory, Hanson Institute, Australia.
Lung Cancer. 2012 Jul;77(1):38-45. doi: 10.1016/j.lungcan.2012.01.017. Epub 2012 Mar 3.
Cytotoxic CD8(+) T-cells mount immune responses to cancer via cytotoxic pathways including granzyme B. Cancer cells are also known to develop immune evasion mechanisms. We hypothesised that lung cancer cells would over-express the granzyme B-inhibitor, proteinase inhibitor-9 (PI-9) and down-regulate granzyme B expression by neighbouring CD8(+) T-cells. We investigated PI-9 expression in lung cancer cell lines, and primary lung cancer cells obtained at curative lung resection from cancer patients with/without chronic obstructive pulmonary disease (COPD). Granzyme B and PI-9 expression was also determined in CD8(+) T-cells from the cancer and non-cancer areas of resected lung tissue and from bronchoalveolar lavage (BAL). We then evaluated the effects of conditioned media from lung cancer cell lines on granzyme B expression and the cytotoxic activity of CD8(+) T-cells. PI-9 was highly expressed in lung cancer cell lines. Increased PI-9 expression was also observed in primary cancer cells vs. epithelial cells from non-cancer tissue or bronchial brushing-derived normal primary large airway epithelial cells. Expression significantly correlated with cancer stage. Significantly reduced granzyme B was noted in CD8(+) T-cells from cancer vs. non-cancer tissue. Granzyme B production by CD8(+) T-cells was reduced in the presence of conditioned media from lung cancer cell lines. Our data suggest that lung cancer cells utilise their increased PI-9 expression to protect from granzyme B-mediated cytotoxicity as an immune evasion mechanism, a function that increases with lung cancer stage.
细胞毒性 CD8(+) T 细胞通过细胞毒性途径（包括颗粒酶 B）对癌症产生免疫反应。癌细胞也被认为会发展出免疫逃避机制。我们假设肺癌细胞会过度表达颗粒酶 B 抑制剂——蛋白酶抑制剂-9 (PI-9)，并通过邻近的 CD8(+) T 细胞下调颗粒酶 B 的表达。我们研究了肺癌细胞系中 PI-9 的表达，以及从接受根治性肺切除术的癌症患者（有无慢性阻塞性肺疾病 (COPD)）的肺部肿瘤和非肿瘤部位获得的原发性肺癌细胞中 PI-9 的表达。还在肿瘤和非肿瘤部位的肺组织切除以及支气管肺泡灌洗 (BAL) 中来自 CD8(+) T 细胞中确定了颗粒酶 B 和 PI-9 的表达。然后，我们评估了来自肺癌细胞系的条件培养基对颗粒酶 B 表达和 CD8(+) T 细胞的细胞毒性活性的影响。PI-9 在肺癌细胞系中高度表达。与非肿瘤组织中的上皮细胞或支气管刷取自正常大气道上皮细胞相比，原发性癌细胞中观察到 PI-9 表达增加。表达与癌症分期显著相关。与非肿瘤组织中的 CD8(+) T 细胞相比，在肿瘤组织中的 CD8(+) T 细胞中明显减少了颗粒酶 B。在存在来自肺癌细胞系的条件培养基的情况下，CD8(+) T 细胞产生的颗粒酶 B 减少。我们的数据表明，肺癌细胞利用其增加的 PI-9 表达来保护免受颗粒酶 B 介导的细胞毒性作为一种免疫逃避机制，这种功能随着肺癌分期的增加而增加。
