Hodge G, Barnawi J, Jurisevic C, Moffat D, Holmes M, Reynolds P N, Jersmann H, Hodge S
Lung Research, Department of Thoracic Medicine, Hanson Institute, Royal Adelaide Hospital, Adelaide, SA, Australia; Department of Medicine, University of Adelaide, Adelaide, SA, Australia.
Clin Exp Immunol. 2014 Oct;178(1):79-85. doi: 10.1111/cei.12392.
There is a limited understanding how of lung cancer cells evade cytotoxic attack. Previously, we have shown reduced production of the cytotoxic mediator granzyme B by CD8(+) T cells in lung cancer tissue. We hypothesized that lung cancer would be further associated with decreased production of granzyme B, perforin and proinflammatory cytokines by other cytotoxic lymphocytes, natural killer (NK) T-like and NK cells, and that this would result from soluble mediators released by the cancer cells. Lung cancer and non-cancer tissue from five patients was identified by experienced pathologists. Tumour necrosis factor (TNF)-α, interferon (IFN)-γ, granzyme B and perforin were measured in CD4 and CD8(+) T, NK T-like cells and NK cells by flow cytometry. Correlation between cancer stage and granzyme B was analysed retrospectively for 21 patients. The effects of soluble factors released by lung cancer cells on production of cytotoxic mediators and cytokines was assessed, and the role of prostaglandin E2 (PGE)2 /COX investigated using indomethacin inhibition. There were significantly decreased percentages of T, NK T-like and NK cells expressing perforin, TNF-α and IFN-γ in cancer versus non-cancer tissue, and of CD8(+) T cells and CD8(+) NK T-like cells expressing granzyme B (e.g. NK T-like cells: non-cancer 30% ± 7 versus cancer 6% ± 2·5). Cancer cells released soluble factors that inhibited granzyme B, perforin and IFN-γ production that was partially associated with the PGE2 /COX2 pathway. Thus, lung cancer is associated with decreased expression of granzyme B, perforin and IFN-γ by infiltrating T cells, NK T-like and NK cells, possibly as a result of soluble factors produced by the cancer cells including PGE2 . This may be an important immune evasion mechanism.
目前对于肺癌细胞如何逃避细胞毒性攻击的了解有限。此前，我们已经表明肺癌组织中CD8(+)T细胞产生的细胞毒性介质颗粒酶B减少。我们推测肺癌还会与其他细胞毒性淋巴细胞、自然杀伤（NK）T样细胞和NK细胞产生颗粒酶B、穿孔素和促炎细胞因子的减少有关，并且这是由癌细胞释放的可溶性介质导致的。由经验丰富的病理学家鉴定了五名患者的肺癌组织和非癌组织。通过流式细胞术检测CD4和CD8(+)T细胞、NK T样细胞和NK细胞中肿瘤坏死因子（TNF）-α、干扰素（IFN）-γ、颗粒酶B和穿孔素的含量。对21名患者进行回顾性分析，分析癌症分期与颗粒酶B之间的相关性。评估了肺癌细胞释放的可溶性因子对细胞毒性介质和细胞因子产生的影响，并使用吲哚美辛抑制来研究前列腺素E2（PGE）2/环氧化酶（COX）的作用。与非癌组织相比，癌症组织中表达穿孔素、TNF-α和IFN-γ的T细胞、NK T样细胞和NK细胞的百分比显著降低，表达颗粒酶B的CD8(+)T细胞和CD8(+)NK T样细胞的百分比也显著降低（例如，NK T样细胞：非癌组织为30%±7，癌症组织为6%±2.5）。癌细胞释放的可溶性因子抑制了颗粒酶B、穿孔素和IFN-γ的产生，这部分与PGE2/COX2途径有关。因此，肺癌与浸润的T细胞、NK T样细胞和NK细胞中颗粒酶B、穿孔素和IFN-γ的表达降低有关，这可能是由于癌细胞产生的可溶性因子包括PGE2所致。这可能是一种重要的免疫逃逸机制。
