IL-8 drives the differentiation of CD74high neutrophils to activate anti-tumor immunity and attenuate NSCLC progression [II]

Neutrophils infiltrated in the tumor microenvironment (TME) are heterogeneous populations associated with the prognosis of cancer and cancer immunotherapy. However, the plasticity and function of heterogeneous neutrophils in the TME of non-small cell lung cancer (NSCLC) remain poorly understood. Here, we show that neutrophils produce high levels of IL-8 which induce the differentiation of CD74highSiglecFlow neutrophils and suppress the generation of CD74lowSiglecFhigh neutrophils in the TME of IL-8-humanized (IL8-hu) KrasLSL-G12DTp53fl/fl (KP) and EGFRT790M/Del-Exon19 (EGFRTD) NSCLC mouse models. The CD74highSiglecFlow neutrophils exhibit antigen cross-presentation activity to augment anti-tumor T cell responses. Consistently, deletion of CD74 in IL8-hu neutrophils attenuates the activation of T cells and exacerbates the progression of NSCLC, whereas treatment of a CD74 agonist promotes anti-tumor T cell activation and enhances the effects of anti-PD1 or Osimertinib therapy in the IL8-hu NSCLC mouse models. In addition, we have found that the CD74highCD63low neutrophils in the TME and peripheral blood of advanced NSCLC patients pheno-copy the CD74highSiglecFlow neutrophils in the TME of NSCLC mice and correlate well with the responsiveness to anti-PD-1 plus chemotherapies. Collectively, these data demonstrate an IL-8-CD74high neutrophil axis that promotes anti-tumor immunity in NSCLC. Overall design: Comparative gene expression profiling analysis of RNA-seq data in neutrophils sorted from tumor-burdened lungs of KrasLSL-G12D/+Tp53fl/flIL8 mice.

浸润于肿瘤微环境（tumor microenvironment, TME）的中性粒细胞是一类异质性群体，与癌症预后及癌症免疫治疗密切相关。然而，非小细胞肺癌（non-small cell lung cancer, NSCLC）肿瘤微环境中异质性中性粒细胞的可塑性与功能，目前仍未得到充分阐明。本研究发现，在IL-8人源化（IL-8-humanized, IL8-hu）KrasLSL-G12DTp53fl/fl（KP）及EGFRT790M/Del-Exon19（EGFRTD）非小细胞肺癌小鼠模型的肿瘤微环境中，中性粒细胞可高水平分泌白细胞介素8（IL-8），该细胞因子可诱导CD74高表达、唾液酸结合免疫球蛋白样凝集素F低表达（CD74highSiglecFlow）中性粒细胞的分化，并抑制CD74低表达、唾液酸结合免疫球蛋白样凝集素F高表达（CD74lowSiglecFhigh）中性粒细胞的生成。CD74highSiglecFlow中性粒细胞具备抗原交叉呈递活性，能够增强抗肿瘤T细胞应答。与之相符的是，在IL8-hu中性粒细胞中敲除CD74，会削弱T细胞的活化并加剧非小细胞肺癌的进展；而给予CD74激动剂治疗，则可促进抗肿瘤T细胞活化，并增强IL8-hu非小细胞肺癌小鼠模型中抗PD-1或奥希替尼（Osimertinib）的治疗效果。此外，本研究还发现，晚期非小细胞肺癌患者肿瘤微环境及外周血中的CD74高表达、CD63低表达（CD74highCD63low）中性粒细胞，在表型上与非小细胞肺癌小鼠肿瘤微环境中的CD74highSiglecFlow中性粒细胞相似，且与抗PD-1联合化疗的响应程度呈显著正相关。综上，本研究数据证实了一条IL-8-CD74high中性粒细胞轴，该轴可促进非小细胞肺癌中的抗肿瘤免疫。整体实验设计：对从KrasLSL-G12D/+Tp53fl/flIL8小鼠荷瘤肺脏中分选得到的中性粒细胞的RNA测序（RNA-seq）数据进行比较基因表达谱分析。