微生物组衍生的TOPOSCORE与原发性耐药转移性黑色素瘤患者化疗后免疫检查点抑制剂再诱导治疗的应答相关。
完整摘要 · 中文译文
背景：对免疫检查点抑制剂（ICI）的原发性耐药仍是转移性黑色素瘤面临的主要挑战。前瞻性多中心PROMIT试验显示，间歇性化疗可使部分患者恢复对ICI再诱导的敏感性。我们研究了在该背景下，以TOPOSCORE为特征的肠道微生物组生态系统状态是否与肿瘤缓解相关。 方法：在II期PROMIT试验（NCT04225390）中，本探索性微生物组分析纳入了24例具有纵向粪便样本的患者。ICI耐药患者接受两个周期的达卡巴嗪化疗，随后进行ICI再诱导。粪便样本接受鸟枪法宏基因组测序。使用TOPOSCORE框架将微生物组生态系统状态分类为SIG1相关或SIG2相关生态系统状态，该框架基于由生态共丰度模式定义的物种相互作用组（SIG）。 结果：基线TOPOSCORE分布和s评分与临床结局无关。在具有完整BL-CTX-ICI采样的9例患者中，6例在整个治疗过程中保持相同的TOPOSCORE类别，3例发生类别改变。在2例部分缓解（PR）患者中，1例始终为SIG2，而另1例在化疗后从SIG2+变为SIG1+，并在ICI再诱导期间恢复为SIG2+。使用各阶段所有可用样本进行的分析同样未显示PR、疾病稳定（SD）和疾病进展（PD）组之间s评分存在显著差异。 结论：基线TOPOSCORE分类不足以预测该队列的治疗结局。纵向TOPOS CORE模式具有异质性，且完整的纵向谱数量较少，无法得出化疗诱导有利微生物组转变的结论。这些探索性发现支持在更大的前瞻性队列中进一步评估微生物组生态系统动力学。
完整摘要 · 英文原文
BACKGROUND: Primary resistance to immune checkpoint inhibitors (ICIs) remains a major challenge in metastatic melanoma. The prospective multicenter PROMIT trial showed that intermittent chemotherapy could restore sensitivity to ICI re-induction in a subset of patients. We investigated whether gut microbiome ecosystem states characterized by TOPOSCORE were associated with tumor response in this setting. METHODS: In the phase II PROMIT trial (NCT04225390), 24 patients with longitudinal stool samples were included in this exploratory microbiome analysis. ICI-resistant patients received two cycles of dacarbazine followed by ICI re-induction. Stool samples underwent shotgun metagenomic sequencing. Microbiome ecosystem states were classified into SIG1- or SIG2-associated ecosystem states using the TOPOSCORE framework, which is based on species-interacting groups (SIGs) defined by ecological co-abundance patterns. RESULTS: Baseline TOPOSCORE distributions and s-scores were not associated with clinical outcome. In the nine patients with complete BL-CTX-ICI sampling, six retained the same TOPOSCORE category throughout treatment and three changed category. Of the two patients with PR, one remained SIG2 throughout, whereas the other changed from SIG2+ to SIG1+ after chemotherapy and returned to SIG2+ during ICI re-induction. Analyses using all available samples at each phase likewise did not show significant differences in s-score among PR, SD, and PD groups. CONCLUSIONS: Baseline TOPOSCORE classification was insufficient to predict treatment outcome in this cohort. Longitudinal TOPOSCORE patterns were heterogeneous, and the small number of complete longitudinal profiles precludes conclusions that chemotherapy induced a favorable microbiome transition. These exploratory findings support further evaluation of microbiome ecosystem dynamics in larger prospective cohorts.