Lyman Melissa R, Mitchell Jacob T, Raghavan Sidharth, Kagohara Luciane T, Huff Amanda L, Haldar Saurav D, Shin Sarah M, Guinn Samantha, Barrett Benjamin, Longway Gabriella, Hernandez Alexei, Coyne Erin M, Yuan Xuan, Andaloori Lalitya, Lai Jiaying, Liu Yun Zhou, Karchin Rachel, Gupta Anuj, Kiemen Ashley L, Forjaz André, Wirtz Denis, Wu Pei-Hsun, Deshpande Atul, Lee Jae W, Armstrong Todd D, Azad Nilofer S, Zimmerman Jacquelyn W, Wood Laura D, Anders Robert A, Thompson Elizabeth D, Jaffee Elizabeth M, Fertig Elana J, Ho Won Jin, Zaidi Neeha
Department of Oncology, Sidney Kimmel Comprehensive Cancer Center.
Convergence Institute.
JCI Insight. 2025 Jun 26;10(15). doi: 10.1172/jci.insight.191595. eCollection 2025 Aug 8.
Pancreatic ductal adenocarcinoma (PDAC) has a poor survival rate due to late detection. PDAC arises from precursor microscopic lesions, termed pancreatic intraepithelial neoplasia (PanIN), that develop at least a decade before overt disease; this provides an opportunity to intercept PanIN-to-PDAC progression. However, immune interception strategies require full understanding of PanIN and PDAC cellular architecture. Surgical specimens containing PanIN and PDAC lesions from a unique cohort of 5 treatment-naive patients with PDAC were surveyed using spatial omics (proteomic and transcriptomic). Findings were corroborated by spatial proteomics of PanIN and PDAC from tamoxifen-inducible KPC mice. We uncovered the organization of lymphoid cells into tertiary lymphoid structures (TLSs) adjacent to PanIN lesions. These TLSs lacked CD21+CD23+ B cells compared with more mature TLSs near the PDAC border. PanINs harbored mostly CD4+ T cells, with fewer Tregs and exhausted T cells than PDAC. Peritumoral space was enriched with naive CD4+ and central memory T cells. These observations highlight the opportunity to modulate the immune microenvironment in PanINs before immune exclusion and immunosuppression emerge during progression into PDAC.
胰腺导管腺癌（PDAC）由于发现较晚，生存率较低。PDAC起源于前驱性微观病变，即胰腺上皮内瘤变（PanIN），这种病变在显性疾病出现前至少十年就已发展；这为拦截PanIN向PDAC的进展提供了机会。然而，免疫拦截策略需要全面了解PanIN和PDAC的细胞结构。我们使用空间组学（蛋白质组学和转录组学）对来自5名未经治疗的PDAC患者的独特队列中含有PanIN和PDAC病变的手术标本进行了研究。来自他莫昔芬诱导的KPC小鼠的PanIN和PDAC的空间蛋白质组学证实了研究结果。我们发现淋巴细胞组织成与PanIN病变相邻的三级淋巴结构（TLS）。与PDAC边界附近更成熟的TLS相比，这些TLS缺乏CD21+CD23+B细胞。PanIN主要含有CD4+T细胞，与PDAC相比，调节性T细胞（Tregs）和耗竭性T细胞较少。肿瘤周围空间富含幼稚CD4+和中枢记忆T细胞。这些观察结果突出了在进展为PDAC期间免疫排斥和免疫抑制出现之前调节PanIN免疫微环境的机会。
