Determination of poor prognostic immune features of tumour microenvironment in non-smoking patients with lung adenocarcinoma
Determination of poor prognostic immune features of tumour microenvironment in non-smoking patients with lung adenocarcinoma
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DOI：
10.1016/j.ejca.2017.08.026
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发表时间：
2017-11-01
影响因子：
8.4
通讯作者：
Kawakami, Yutaka
中科院分区：
文献类型：
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作者：
Kinoshita, Tomonari;Kudo-Saito, Chie;Kawakami, Yutaka
我们先前已经证明，在非小细胞肺癌(NSCLC)中，肿瘤浸润性CD8(+)T细胞的预后意义因组织类型和患者吸烟习惯的不同而显著不同。这项工作提示，在非吸烟者的腺癌免疫抑制微环境中，浸润性CD8(+)T细胞可能没有被充分激活。为了了解NSCLC的免疫原性微环境，我们采用免疫组织化学方法对免疫细胞进行了全面的表征(n=234)，并使用遗传分析方法对免疫相关基因的表达进行了评估(n=58)。我们发现在非腺癌患者中，表达干扰素-γ和颗粒酶的活化CD8(+)T细胞的高渗透与术后生存有关。相反，CD8(+)T细胞积聚被认为是腺癌患者，特别是非吸烟者预后较差的因素。在各种免疫调节基因高表达的微环境中，浸润性CD8(+)T细胞的活化程度明显降低。在非吸烟者的腺癌中，CD8(+)FOXP3(+)T细胞和免疫功能紊乱的CD8(+)GATA3(+)T细胞增加。表达趋化因子受体4(CCR4)的CD8(+)FOXP3(+)调节性T细胞和表达趋化因子配体(CCL17)的CD163(+)M2样巨噬细胞也在非吸烟者的腺癌中显著聚集。这些特有的免疫细胞可能通过在不吸烟的肺腺癌患者中创造免疫抑制微环境来促进肿瘤的进展。我们的发现可能有助于完善目前个性化免疫治疗的策略，包括免疫检查点阻断治疗非小细胞肺癌。(C)2017爱思唯尔有限公司。保留所有权利。
We have previously demonstrated that the prognostic significance of tumour-infiltrating CD8(+) T cells significantly differs according to histological type and patient smoking habits in non-small cell lung cancer (NSCLC). This work suggested that infiltrating CD8(+) T cells may not be activated sufficiently in the immunosuppressive microenvironment in non-smokers with adenocarcinoma. To understand the immunogenic microenvironment in NSCLC, we characterised immune cells comprehensively by performing an immunohistochemical evaluation using an alternative counting method and multicolour staining method (n = 234), and assessed immune-related gene expression by using genetic analytical approaches (n = 58). We found that high infiltration of activated CD8(+) T cells expressing interferon gamma (IFN-gamma) and granzyme was correlated with postoperative survival in patients with non-adenocarcinoma. On the contrary, CD8(+) T-cell accumulation was identified as a worse prognostic factor in patients with adenocarcinoma, particularly in non-smokers. Infiltrating CD8(+) T cells were significantly less activated in this microenvironment with high expression of various immunoregulation genes. Potentially immunoregulatory CD8(+) FOXP3(+) T cells and immunodysfunctional CD8(+) GATA3(+) T cells were increased in adenocarcinoma of non-smokers. CD8(+) FOXP3(+) regulatory T cells expressing chemokine receptor-4 (CCR4)-and chemokine ligand (CCL17)-expressing CD163(+) M2-like macrophages also accumulated correlatively and significantly in adenocarcinoma of non-smokers. These characteristic immune cells may promote tumour progression possibly by creating an immunosuppressive microenvironment in non-smoking patients with lung adenocarcinoma. Our findings may be helpful for refining the current strategy of personalised immunotherapy including immune-checkpoint blockade therapy for NSCLC. (C) 2017 Elsevier Ltd. All rights reserved.