Wong Matthew K, Boukhaled Giselle M, Armstrong Eric, Liu Rachel, Heirali Alya A, Yee Noelle R, Tsang Jinny, Spiliopoulou Pavlina, Schneeberger Pierre H H, Wang Ben X, Cochrane Kyla, Sherriff Keith, Allen-Vercoe Emma, Siu Lillian L, Spreafico Anna, Coburn Bryan
Department of Immunology, University of Toronto, Toronto, Ontario, Canada.
Tumor Immunotherapy Program, Princess Margaret Cancer Centre, University Health Network, Toronto, Ontario, Canada.
J Immunother Cancer. 2025 Mar 22;13(3):e010681. doi: 10.1136/jitc-2024-010681.
Gut microbiome modulation has shown promise in its potential to treat cancer in combination with immunotherapy. Mechanistically, the pathways and routes by which gut microbiota may influence systemic and antitumor immunity remain uncertain. Here, we used blood and stool samples from Microbial Ecosystem Therapeutic 4 (MET4)-IO, an early-phase trial testing the safety and engraftment of the MET4 bacterial consortium in immune checkpoint inhibitor recipients, to assess how MET4 may affect systemic immunity.
Circulating antibody responses induced by MET4 were assessed using an antimicrobial antibody flow cytometry assay on pretreatment and post-treatment plasma. Antibody responses were associated with taxonomic changes in stool identified by metagenomic sequencing. Mass cytometry was performed on peripheral blood mononuclear cells to identify shifts in circulating immune subsets associated with antibody responses.
Increases in circulating anti-MET4 immunoglobulin G (IgG) responses were measured by flow cytometry post-consortium treatment in MET4 recipients, but not untreated control participants, with five individuals displaying notably higher antibody responses. Stronger IgG responses were associated with greater increases in multiple taxa, including MET4 microbe , which was previously linked with immune checkpoint response. However, these taxa were not enriched in the IgG-bound fraction post-MET4 treatment. Greater increases in circulating B cells and FoxP3 CD4 T cells post-MET4 treatment were observed in the blood of high IgG responders, while CD14 and CD16 monocyte populations were decreased in these individuals.
These results demonstrate the induction of treatment-specific circulating humoral immunity by a bacterial consortium and suggest potential mechanisms by which gut microbes may contribute to antitumor immunity.
肠道微生物群调节在与免疫疗法联合治疗癌症方面已显示出潜力。从机制上讲，肠道微生物群可能影响全身和抗肿瘤免疫的途径和路线仍不确定。在此，我们使用了微生物生态疗法4（MET4）-IO的血液和粪便样本，这是一项早期试验，测试MET4细菌联合体在免疫检查点抑制剂接受者中的安全性和植入情况，以评估MET4如何影响全身免疫。
使用抗菌抗体流式细胞术检测预处理和治疗后血浆中MET4诱导的循环抗体反应。抗体反应与宏基因组测序确定的粪便分类学变化相关。对外周血单个核细胞进行质谱流式细胞术，以确定与抗体反应相关的循环免疫亚群的变化。
通过流式细胞术检测，MET4接受者在联合体治疗后循环抗MET4免疫球蛋白G（IgG）反应增加，但未治疗的对照参与者没有增加，有五名个体显示出明显更高的抗体反应。更强的IgG反应与多个分类群的更大增加相关，包括MET4微生物，其先前与免疫检查点反应有关。然而，这些分类群在MET4治疗后的IgG结合部分中并未富集。在高IgG反应者的血液中，观察到MET4治疗后循环B细胞和FoxP3 CD4 T细胞有更大增加，而这些个体中的CD14和CD16单核细胞群体减少。
这些结果证明了细菌联合体可诱导治疗特异性循环体液免疫，并提示了肠道微生物可能有助于抗肿瘤免疫的潜在机制。
