Tang Di, Zhang Duo, Heng Yu, Zhu Xiao-Ke, Lin Han-Qing, Zhou Jian, Tao Lei, Lu Li-Ming
Department of Otorhinolaryngology and ENT Institute, Eye & ENT Hospital, Fudan University, Shanghai, People's Republic of China.
Shanghai Institute of Immunology, Shanghai Jiaotong University School of Medicine, Shanghai, People's Republic of China.
J Inflamm Res. 2022 Feb 16;15:1079-1097. doi: 10.2147/JIR.S347777. eCollection 2022.
Chronic inflammation contributes to tumor initiation, progression, and immune escape. Neutrophils are the major component of inflammatory response and participate in the tumorigenesis process. However, compared to other immune cells in the tumor microenvironment of laryngeal squamous cell carcinoma (LSCC), neutrophils, especially the tumor-associated neutrophils (TANs), have not yet been comprehensively explored. The mechanism for regulating the crosstalk between TANs and tumor cells still remains unclear.
The distribution profiles and phenotypic features of neutrophils and other inflammatory immune cell populations from a large LSCC patient cohort were systemically analyzed. Co-culturing of peripheral blood associated neutrophils (PANs) and TANs with PBMCs was performed, and the immunosuppression effect on T-cells was examined.
LSCC microenvironment is highly inflammatory with remarkable TANs infiltration, which is often associated with unfavorable prognosis and advanced clinical stage. We find that TANs in LSCC display morphologically immature and lower apoptosis, exhibit distinctively immunosuppressive phenotype of high PD-L1, and suppress CD8 T lymphocytes proliferation and activation. We subsequently discover that PD-L1TANs induced by LSCC-derived GM-CSF potently impair CD8 T-cells proliferation and cytokines production function, which are partially blocked by a PD-L1-neutralizing antibody. Clinical data further support GM-CSF as an unfavorable prognostic biomarker and reveal a potential association with inflammatory immune cell infiltration, in particular neutrophils.
Tumor-infiltrating PD-L1+ neutrophils induced by LSCC-derived GM-CSF suppress T cell proliferation and activation in the inflammatory microenvironment of LSCC and predict unfavorable prognosis. These TANs cripple antitumor T cell immunity and promote tumor progression. Our findings provide a basis for targeting PD-L1+TANs or GM-CSF as a new immunotherapeutic strategy for LSCC.
慢性炎症促进肿瘤的起始、进展和免疫逃逸。中性粒细胞是炎症反应的主要成分，并参与肿瘤发生过程。然而，与喉鳞状细胞癌（LSCC）肿瘤微环境中的其他免疫细胞相比，中性粒细胞，尤其是肿瘤相关中性粒细胞（TANs），尚未得到全面研究。TANs与肿瘤细胞之间相互作用的调节机制仍不清楚。
系统分析了来自大量LSCC患者队列的中性粒细胞和其他炎性免疫细胞群体的分布特征和表型特征。进行外周血相关中性粒细胞（PANs）和TANs与外周血单核细胞（PBMCs）的共培养，并检测对T细胞的免疫抑制作用。
LSCC微环境具有高度炎症性，伴有显著的TANs浸润，这通常与不良预后和晚期临床分期相关。我们发现LSCC中的TANs形态上不成熟且凋亡率较低，表现出高PD-L1的明显免疫抑制表型，并抑制CD8 T淋巴细胞的增殖和活化。我们随后发现，LSCC来源的粒细胞-巨噬细胞集落刺激因子（GM-CSF）诱导的PD-L1+TANs强烈损害CD8 T细胞的增殖和细胞因子产生功能，而PD-L1中和抗体可部分阻断这种作用。临床数据进一步支持GM-CSF作为不良预后生物标志物，并揭示其与炎性免疫细胞浸润，特别是中性粒细胞的潜在关联。
LSCC来源的GM-CSF诱导的肿瘤浸润性PD-L1+中性粒细胞在LSCC炎性微环境中抑制T细胞增殖和活化，并预示不良预后。这些TANs削弱抗肿瘤T细胞免疫并促进肿瘤进展。我们的研究结果为将PD-L1+TANs或GM-CSF作为LSCC的新免疫治疗策略提供了依据。
