Fan Zhijun, Yi Zheng, Li Sheng, He Junjun
Department of Cardiothoracic Surgery, The People's Hospital of Liuyang, Changsha, China.
Department of Gastrointestinal Surgery, The Central Hospital of Shaoyang, Shaoyang, China.
BMC Biotechnol. 2025 Apr 16;25(1):30. doi: 10.1186/s12896-025-00963-9.
Parabacteroides distasonis (P. distasonis) could regulate inflammatory markers, promote intestinal barrier integrity, and block tumor formation in colon. However, the regulatory effect of P. distasonis on non-small cell lung cancer (NSCLC) remains unknown. This study aimed to investigate the regulatory effect of P. distasonis on NSCLC and its impact on tumor immunity.
We first established a mouse model of Lewis lung cancer, and administered P. distasonis and intrabitoneal injection of anti-mouse PD-1 monoclonal antibody to assess the impact of P. distasonis on tumor immunity, and mouse intestinal barrier. Then, we explored the effect of P. distasonis on CD8T cells and CXCL9 secretion mediated by tumor-associated macrophages (TAM). We used the TLR1/2 complex inhibitor CPT22 to evaluate its effect on macrophage activation. Finally, we explored the effect of P. distasonis on CD8T cells and CXCL9 secreted by TAM in vivo.
In vivo, P. distasonis enhanced anti-tumor effects of anti-PD-1 in NSCLC mice, improved intestinal barrier integrity, recruited macrophages, and promoted M1 polarization. In vitro, CD86 and iNOS levels in BMDM were elevated and CD206 and Arg1 levels were suppressed in membrane fraction of P. distasonis (PdMb) group in comparison to Control group. With additional CPT22 pre-treatment, the levels of CD86 and iNOS in BMDM were reduced, and the levels of CD206 and Arg1 were increased. Compared to PBS group, P. distasonis group exhibited higher proportion of CD8T cells in tumor tissues, along with increased positive proportion of GZMB and IFN-γ in CD8T cells. Additionally, in comparison to Control group, PdMb group showed an elevated proportion of GZMBT and IFN-γT cells within CD8T cells, and secretion of IFN-γ, TNF-α, perforin, and GZMB in CD8T cell supernatant increased. Moreover, the proportion of CXCL9F4/80 macrophages in tumor tissues was higher in P. distasonis group compared to PBS group. In comparison to Control group, CXCL9 protein level in BMDM and CXCL9 secretion level in BMDM supernatant were increased in PdMb group. Finally, P. distasonis enhanced CD8T cell activity by secreting CXCL9 from macrophages in vivo.
P. distasonis promoted CXCL9 secretion of TAM and enhanced CD8T cell activity to trigger anti-tumor immunity against anti-PD-1 treatment in NSCLC mice.
狄氏副拟杆菌（P. distasonis）可调节炎症标志物，促进肠道屏障完整性，并阻止结肠肿瘤形成。然而，P. distasonis对非小细胞肺癌（NSCLC）的调节作用尚不清楚。本研究旨在探讨P. distasonis对NSCLC的调节作用及其对肿瘤免疫的影响。
我们首先建立了Lewis肺癌小鼠模型，并给予P. distasonis和腹腔注射抗小鼠PD-1单克隆抗体，以评估P. distasonis对肿瘤免疫和小鼠肠道屏障的影响。然后，我们探讨了P. distasonis对肿瘤相关巨噬细胞（TAM）介导的CD8T细胞和CXCL9分泌的影响。我们使用TLR1/2复合物抑制剂CPT22来评估其对巨噬细胞活化的影响。最后，我们在体内探讨了P. distasonis对TAM分泌的CD8T细胞和CXCL9的影响。
在体内，P. distasonis增强了抗PD-1在NSCLC小鼠中的抗肿瘤作用，改善了肠道屏障完整性，招募了巨噬细胞，并促进了M1极化。在体外，与对照组相比，P. distasonis（PdMb）组骨髓来源的巨噬细胞（BMDM）中CD86和诱导型一氧化氮合酶（iNOS）水平升高，而膜部分中CD206和精氨酸酶1（Arg1）水平受到抑制。额外的CPT22预处理后，BMDM中CD86和iNOS水平降低，而CD206和Arg1水平升高。与PBS组相比，P. distasonis组肿瘤组织中CD8T细胞比例更高，CD8T细胞中颗粒酶B（GZMB）和干扰素-γ（IFN-γ）的阳性比例增加。此外，与对照组相比，PdMb组CD8T细胞内GZMB+和IFN-γ+细胞的比例升高，CD8T细胞上清液中IFN-γ、肿瘤坏死因子-α（TNF-α）、穿孔素和GZMB的分泌增加。此外，与PBS组相比，P. distasonis组肿瘤组织中CXCL9+F4/80巨噬细胞的比例更高。与对照组相比，PdMb组BMDM中CXCL9蛋白水平和BMDM上清液中CXCL9分泌水平升高。最后，P. distasonis通过在体内从巨噬细胞分泌CXCL9来增强CD8T细胞活性。
P. distasonis促进TAM的CXCL9分泌并增强CD8T细胞活性，以触发NSCLC小鼠对抗PD-1治疗的抗肿瘤免疫。
