Disruption of Fibroblast MYD88 Signaling Promotes Antitumor Immunity in Pancreatic Ductal Adenocarcinoma [scRNAseq_ICBCA4948tx]

Pancreatic ductal adenocarcinoma (PDAC) continues to carry a dismal prognosis. The disease is characterized by a uniquely dense fibrotic matrix generated by cancer-associated fibroblasts (CAFs). We have previously demonstrated that fibroblast-driven chronic inflammation suppresses T cell function through a MYD88-dependent mechanism. While extensively studied in myeloid cells, the role of MYD88 signaling in CAFs and its effects on PDAC remain poorly understood. In this study, we identify a MYD88-driven inflammatory CAF population in PDAC using a combination of bulk, single-cell, and spatial transcriptomic studies. Using an innovative collagen gel implantation model, we demonstrate that loss of MYD88 in CAFs enhances T cell infiltration and suppresses tumor growth. Combining MYD88 inhibition with immune checkpoint blockade significantly reduces tumor size and enhances antitumor immune responses, underscoring its potential as a therapeutic target in PDAC. Following implantation of the KPC-seeded collagen gels into C57BL/6J mice, mice underwent treatment with ICB alone, ICB with CA-4948, and control. Tumors were harvested and dissociated into single cells using the Miltenyi Mouse Tumor Dissociation Kit and analyzed using scRNA-seq.

胰腺导管腺癌（PDAC）始终预后极差。该疾病的特征是由癌症相关成纤维细胞（CAFs）产生的独特致密纤维化基质。我们此前已证实，成纤维细胞介导的慢性炎症可通过依赖MYD88的机制抑制T细胞功能。尽管MYD88信号通路在髓系细胞中已被广泛研究，但其在CAFs中的作用以及对PDAC的影响仍不甚明确。本研究通过整合批量转录组、单细胞转录组及空间转录组分析，在PDAC中鉴定出一类由MYD88驱动的炎症性CAF亚群。本研究利用创新的胶原蛋白凝胶植入模型，证实CAFs中MYD88缺失可增强T细胞浸润并抑制肿瘤生长。将MYD88抑制疗法与免疫检查点阻断（immune checkpoint blockade, ICB）联合使用，可显著缩小肿瘤体积并增强抗肿瘤免疫应答，凸显其作为PDAC治疗靶点的潜力。将接种KPC细胞的胶原蛋白凝胶植入C57BL/6J小鼠体内后，小鼠分别接受单一ICB治疗、ICB联合CA-4948治疗以及对照处理。实验人员采用Miltenyi小鼠肿瘤组织解离试剂盒将肿瘤组织解离为单细胞悬液，并通过单细胞RNA测序（single-cell RNA sequencing, scRNA-seq）进行分析。