Acidovorax temperans skews neutrophil maturation and polarizes Th17 cells to promote lung adenocarcinoma development

Dysbiosis, or changes within the microbiome, is a common feature of solid tumors, however whether this dysbiosis directly contributes to tumor development is largely unknown. We previously characterized the lung cancer microbiome and identified the Gram-negative Acidovorax temperans as enriched in tumors and associated with smoking status and TP53 mutations. To determine if A. temperans exposure could contribute to the development of lung cancer, we investigated its effect in an animal model of lung adenocarcinoma driven by mutant Kras and Tp53 alleles. This revealed A. temperans exposure accelerates tumor development and burden through infiltration of proinflammatory cells in the lungs. Neutrophils exposed to A. temperans displayed a mature, pro-tumorigenic phenotype with increased cytokine signaling, with a global shift away from IL-1β signaling. Neutrophil to monocyte and macrophage signaling promoted maturation of the latter cell types which upregulated MHC II to activate CD4+ T cells. Activated T cells were then polarized to an IL-17A+ phenotype detectable in CD4+ and γδ populations. Furthermore, T17 cells shared a common gene expression profile predictive of poor survival in human LUAD cases. These data indicate a clear role for microbiota-induced inflammation as a key mechanism in the development of lung cancer, demonstrating that dysbiosis contributes to tumor growth. CD45+ cells were sorted by FACS from tumor tissue within the mutant K-ras/p53 (KP) mouse model of lung adenocarcinoma and sent for scRNA-seq

菌群失调（Dysbiosis），即微生物组内的改变，是实体瘤的常见特征；然而这种菌群失调是否直接促进肿瘤发生，目前尚不清楚。我们此前已完成肺癌微生物组的表征分析，鉴定出革兰氏阴性菌嗜温食酸菌（Acidovorax temperans）在肿瘤组织中富集，且与吸烟状态及TP53突变相关。为明确嗜温食酸菌暴露是否可促进肺癌发生，我们在由突变型Kras与Tp53等位基因驱动的肺腺癌动物模型中，探究了该菌的作用效应。实验结果表明，嗜温食酸菌暴露可通过肺部促炎细胞浸润，加速肿瘤发生发展并加重肿瘤负荷。暴露于嗜温食酸菌的中性粒细胞呈现出成熟的促肿瘤表型，伴随细胞因子信号通路增强，且整体转向脱离白细胞介素1β（IL-1β）信号通路。中性粒细胞与单核细胞、巨噬细胞间的信号通路可促进后两类细胞的成熟，后者会上调主要组织相容性复合体II（MHC II）以激活CD4阳性T细胞（CD4+ T cells）。活化的T细胞随后极化为白细胞介素17A阳性（IL-17A+）表型，该表型可在CD4阳性T细胞及γδ T细胞群中被检测到。此外，T17细胞具有共同的基因表达特征，该特征可预测人类肺腺癌（LUAD）患者的不良预后。上述数据明确证实，微生物组诱导的炎症是肺癌发生的关键机制，证明菌群失调可促进肿瘤生长。我们从突变型K-ras/p53（KP）肺腺癌小鼠模型的肿瘤组织中，通过荧光激活细胞分选术（FACS）分选出CD45阳性细胞，并将其送检进行单细胞RNA测序（scRNA-seq）。