Kinoshita Tomonari, Kudo-Saito Chie, Muramatsu Reiko, Fujita Tomonobu, Saito Miyuki, Nagumo Haruna, Sakurai Toshiharu, Noji Shinobu, Takahata Emi, Yaguchi Tomonori, Tsukamoto Nobuo, Hayashi Yuichiro, Kaseda Kaoru, Kamiyama Ikuo, Ohtsuka Takashi, Tomizawa Kenji, Shimoji Masaki, Mitsudomi Tetsuya, Asamura Hisao, Kawakami Yutaka
Division of Cellular Signaling, Institute for Advanced Medical Research, Keio University School of Medicine, 35 Shinanomachi, Shinjuku, Tokyo 1608582, Japan; Division of General Thoracic Surgery, Department of Surgery, Keio University School of Medicine, 35 Shinanomachi, Shinjuku, Tokyo 1608582, Japan.
Division of Molecular & Cellular Medicine, Group for Translational Research, National Cancer Center Research Institute, 5-1-1 Tsukiji, Chuo, Tokyo 1040045, Japan.
Eur J Cancer. 2017 Nov;86:15-27. doi: 10.1016/j.ejca.2017.08.026. Epub 2017 Sep 23.
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-γ) 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. CD4 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.
我们之前已经证明，在非小细胞肺癌（NSCLC）中，肿瘤浸润性CD8 T细胞的预后意义根据组织学类型和患者吸烟习惯的不同而有显著差异。这项研究表明，在腺癌非吸烟者的免疫抑制微环境中，浸润的CD8 T细胞可能没有得到充分激活。为了了解NSCLC中的免疫原性微环境，我们通过使用替代计数方法和多色染色方法进行免疫组织化学评估（n = 234），全面表征免疫细胞，并使用基因分析方法评估免疫相关基因表达（n = 58）。我们发现，表达干扰素γ（IFN-γ）和颗粒酶的活化CD8 T细胞的高浸润与非腺癌患者的术后生存相关。相反，CD8 T细胞的积聚被确定为腺癌患者，尤其是非吸烟者的一个更差的预后因素。在这种具有多种免疫调节基因高表达的微环境中，浸润的CD8 T细胞的活化明显较少。在非吸烟者的腺癌中，潜在的免疫调节性CD8 FOXP3 T细胞和免疫功能失调的CD8 GATA3 T细胞增加。表达趋化因子受体4（CCR4）的CD4 FOXP3调节性T细胞和表达趋化因子配体（CCL17）的CD163 M2样巨噬细胞在非吸烟者的腺癌中也相应且显著地积聚。这些特征性免疫细胞可能通过在非吸烟肺腺癌患者中创造免疫抑制微环境来促进肿瘤进展。我们的发现可能有助于完善当前包括NSCLC免疫检查点阻断疗法在内的个性化免疫治疗策略。
