PO.CL01.02 · 临床研究

Smad缺陷通过改变胰腺腺癌的免疫-基质微环境影响化疗应答

Smad deficiency impacts chemotherapeutic responses through alterations in immuno-stromal microenvironment of pancreatic adenocarcinoma

编号 1048 展板 16 时间 4/19 02:00–05:00 区域 Section 41 主讲 Chih Chieh (Jack) Yen, MD;PhD

分会场 Biomarkers Predictive of Therapeutic Benefit 2

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作者与单位 Authors & Affiliations

Chih Chieh Yen¹, Ying Jui Chao², Ping Jui Su², Ting Kai Liao², Wei Hsun Lu², Zhe Wei Hsu³, Chien Jui Huang⁴, I Ting Liu¹, Wen Yen Huang⁵, Yan Shen Shan², Chia Jui Yen¹

¹Department of Oncology, National Cheng Kung University Hospital, Tainan, Taiwan,²Department of Surgery, National Cheng Kung University Hospital, Tainan, Taiwan,³Department of Pathology, National Cheng Kung University Hospital, Tainan, Taiwan,⁴Division of Gastroenterology and Hepatology, Department of Internal Medicine, National Cheng Kung University Hospital, Tainan, Taiwan,⁵Institute of Clinical Medicine, National Cheng Kung University, Tainan, Taiwan

摘要 Abstract

中文摘要

背景：胰腺腺癌（PDAC）是一种预后极差的毁灭性癌症。术前化疗（PreOP_CT）已重塑了治疗范式。然而，影响治疗应答以及免疫/基质改变的因素尚未确立。Smad家族通过转化生长因子-β（TGFbeta）轴发挥关键的生物学作用并影响肿瘤微环境（TME），但其与治疗应答的相关性尚未得到充分探索。方法：我们探索了一个接受PreOP_CT的可切除PDAC患者前瞻性队列。评估TGFbeta轴中Smad家族的基因组畸变并比较其临床结局。单细胞RNA测序描绘了Smad缺陷型与Smad功能完整型肿瘤中的免疫-基质改变。结果：106例患者中有15例为Smad缺陷型肿瘤，与功能完整型相比表现出更低的肿瘤消退、更高的转移进展和更差的生存。Smad缺陷型肿瘤中观察到SMAD4或TGFBR2/3突变。Smad缺陷与肿瘤浸润免疫细胞（TIMCs）和癌症相关成纤维细胞（CAFs）的不同富集相关。总体而言，炎症性和抗原呈递性CAFs在缺陷型肿瘤中具有特征性，并表现出免疫逃逸作用。结论：Smad缺陷影响PreOP_CT治疗的PDAC的治疗和手术结局。Smad家族可能影响TIMCs和CAFs，增强免疫逃逸性和促纤维化的TME。这些结果为PDAC中PreOP治疗的推定生物标志物提供了见解。

查看英文原文 English abstract

Background: Pancreatic adenocarcinoma (PDAC) is a devastating cancer with a dismal prognosis. Preoperative chemotherapy (PreOP_CT) has reshaped the treatment paradigm. However, factors influencing therapeutic responses and immune/stromal alterations have not been established. Smad family exerts pivotal biological actions through transforming growth factor-beta (TGFbeta) axis and affects tumor microenvironment (TME), yet the correlation with therapeutic responses has not been fully explored. Methods: We explored a prospective cohort of patients with resectable PDAC who received PreOP_CT. Genomic aberrations of the Smad family in the TGFbeta axis were assessed and compared for clinical outcomes. Single-cell RNA sequencing delineated the immuno-stromal alterations in Smad-deficient vs. -proficient tumors. Results: Fifteen of 106 patients had Smad-deficient tumors and showed reduced tumor regression, higher metastatic progression and adverse survival as compared with -proficient ones. SMAD4 or TGFBR2/3 mutations were observed in Smad-deficient tumors. Smad deficiency correlated with different enrichments of tumor-infiltrating immune cells (TIMCs) and cancer-associated fibroblasts (CAFs). Collectively, inflammatory and antigen-presenting CAFs were distinctive in the deficient tumors and presented with immune evasive actions. Conclusion: Smad deficiency influences therapeutic and surgical outcomes in PreOP_CT-treated PDAC. The Smad family potentially affects TIMCs and CAFs, potentiating an immune evasive and profibrotic TME. The results provide insight into a putative biomarker for PreOP therapies in PDAC.

利益披露 Disclosure

C. Yen, None.. Y. Chao, None.. P. Su, None.. T. Liao, None.. W. Lu, None.. Z. Hsu, None.. C. Huang, None.. I. Liu, None.. W. Huang, None.. Y. Shan, None.. C. Yen, None.

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