Extracellular Matrix-MYCAF Signatures Correlate with Resistance to Neoadjuvant aPD-L1 Immune Checkpoint Inhibition with Durvalumab + Metformin in HPV+ HNSCC.

Metformin may synergize with ICIs, offering promise to improve response rates.

二甲双胍可能与ICI具有协同作用，有望提高反应率。

We leveraged multiomic data from a randomized, presurgical neoadjuvant trial (NCT03618654) evaluating a single infusion of the anti-PD-L1 ICI durvalumab with or without daily, standard dose metformin in previously untreated, nondiabetic patients with HNSCC to understand predictors of response and the effect of combination therapy.

我们利用了一项随机、术前新辅助试验（NCT03618654）的多组学数据，该试验评估了单次输注抗PD-L1免疫检查点抑制剂durvalumab，以及durvalumab联合每日标准剂量的二甲双胍在之前未接受治疗、非糖尿病的头颈部鳞状细胞癌（HNSCC）患者中的效果，以了解反应的预测因素和联合治疗的效果。

patients_and_methods

Clinical, pathologic, and correlative data were analyzed to investigate response and resistance mechanisms.

分析了临床、病理和相关数据，以研究反应和耐药机制。

We present an in-depth multiomic analysis of primary tumor specimens to study treatment response/resistance in human papillomavirus-positive HNSCC.

我们对原发肿瘤样本进行了深入的多组学分析，以研究人类乳头瘤病毒阳性头颈部鳞状细胞癌的治疗反应和耐药性。

Results

Baseline samples revealed that myofibroblastic cancer-associated fibroblast and extracellular matrix signatures were enriched in durvalumab plus metformin nonresponders, which were localized to the leading tumor edge on spatial transcriptomics.

基线样本显示，肌成纤维细胞癌相关成纤维细胞和细胞外基质特征在durvalumab 加上二甲双胍的非应答者中富集，这些特征在空间转录组学中定位在肿瘤前沿。

In contrast, baseline responder samples were enriched for the Langerhans-like dendritic cell (DC) state and IFN signatures.

相比之下，基线反应样本中富含朗格汉斯样树突状细胞（DC）状态和干扰素（IFN）信号特征。

Treatment increased intratumoral CD8+ T-cell and IFN signatures and peripheral blood CCL2 levels.

治疗增加了肿瘤内CD8+ T细胞和干扰素（IFN）信号特征以及外周血CCL2水平。

Responders demonstrated macrophage and DC enrichment and antigen processing and presentation upregulation.

反应者显示出巨噬细胞和树突状细胞的富集以及抗原处理和呈递的上调。

Enrichment of cell cycle-related gene sets, specifically the MYC targets V1 hallmark gene set, correlated with nonresponse.

细胞周期相关基因集的富集，特别是MYC靶点V1标志基因集，与无反应相关。

Conclusions

Early response and resistance dynamics for durvalumab plus metformin in human papillomavirus-positive HNSCC reveal baseline extracellular matrix-myofibroblastic cancer-associated fibroblast as predictive of nonresponse.

早期反应和耐药性动态揭示了在人类乳头瘤病毒阳性头颈部鳞状细胞癌中，使用durvalumab加二甲双胍治疗时，基线时细胞外基质-肌成纤维细胞癌相关成纤维细胞的存在是预测非反应的指标。

In contrast, responders were distinguished by baseline enrichment in the Langerhans-like DC state and posttreatment antigen-presenting gene sets.

相比之下，反应者的特点是基线时朗格汉斯样树突状细胞状态和治疗后抗原呈递基因集的富集。