寻找生物标志物以鉴定免疫检查点抑制剂（ICI）治疗的理想候选人是基础性工作。本研究中，我们分析外周血CD3+HLADR+细胞（激活的T细胞）作为ICI治疗的一种新型生物标志物，并研究其与某些肠道微生物种类的关联，以指示个体的治疗效果。我们对进行固体恶性肿瘤的70名患者进行了外周单个核细胞血细胞（PBMCs）的流式细胞术分析，以量化循环CD3+细胞上的HLA-DR。我们对37名患者的粪便样本进行了16s-rRNA测序，以评估肠道菌群的相对丰度。治疗开始前，CD3+HLADR+细胞的频率较高的患者显示出明显降低的肿瘤反应和总生存期（OS），较差的反应，并且在受到ICI治疗后经历了较少的毒副作用。因此，CD3+HLADR+细胞频率高于18.55%的患者，其中位OS仅为132天，而低于该值的患者为569天。治疗期间CD3+HLADR+细胞计数逐渐增加的患者，其OS明显改善。一个由CD3+HLADR+细胞和中性粒细胞-淋巴细胞比值（NLR）组成的免疫标志评分，在治疗前和治疗期间都具有高度显著的预测OS能力。当与Burkholderiales目的相对丰度和Bacteroides vulgatus菌种的相对丰度结合时，两种免疫-微生物评分显示出了有希望的预测和预后能力。我们确定了CD3+HLADR+细胞的频率和动态作为易于获取的预后标志物，用于预测对ICI的治疗结果，并研究其与调节免疫的肠道菌群物种的关联。包括CD3+HLADR+细胞、NLR和Burkholderiales目或Bacteroides vulgatus菌种相对丰度的两个前所未有的免疫-微生物评分能够准确预测对免疫检查点阻断的OS。版权所有 © 2023 Gorgulho, Roderburg, Beier, Bokemeyer, Brümmendorf, Luedde and Loosen.

The search for biomarkers to identify ideal candidates for immune checkpoint inhibitor (ICI) therapy is fundamental. In this study, we analyze peripheral blood CD3+HLADR+ cells (activated T-cells) as a novel biomarker for ICI therapy and how its association to certain gut microbiome species can indicate individual treatment outcomes.Flow cytometry analysis of peripheral mononuclear blood cells (PBMCs) was performed on n=70 patients undergoing ICI therapy for solid malignancies to quantify HLA-DR on circulating CD3+ cells. 16s-rRNA sequencing of stool samples was performed on n=37 patients to assess relative abundance of gut microbiota.Patients with a higher frequency of CD3+HLADR+ cells before treatment initiation showed a significantly reduced tumor response and overall survival (OS), a worst response and experienced less toxicities to ICI therapy. As such, patients with a frequency of CD3+HLADR+ cells above an ideal cut-off value of 18.55% had a median OS of only 132 days compared to 569 days for patients below. Patients with increasing CD3+HLADR+ cell counts during therapy had a significantly improved OS. An immune signature score comprising CD3+HLADR+ cells and the neutrophil-lymphocyte ratio (NLR) was highly significant for predicting OS before and during therapy. When allied to the relative abundance of microbiota from the Burkholderiales order and the species Bacteroides vulgatus, two immune-microbial scores revealed a promising predictive and prognostic power.We identify the frequencies and dynamics of CD3+HLADR+ cells as an easily accessible prognostic marker to predict outcome to ICIs, and how these could be associated with immune modulating microbiome species. Two unprecedented immune-microbial scores comprising CD3+HLADR+, NLR and relative abundance of gut bacteria from the Burkhorderiales order or Bacteroides vulgatus species could accurately predict OS to immune checkpoint blockade.Copyright © 2023 Gorgulho, Roderburg, Beier, Bokemeyer, Brümmendorf, Luedde and Loosen.