Defining the spatial distribution of extracellular adenosine revealed a myeloid-dependent immunosuppressive microenvironment in pancreatic ductal adenocarcinoma-猫眼课题宝

DOI：

10.1101/2022.05.24.493238

发表时间：

2022-11

期刊：

bioRxiv

影响因子：

通讯作者：

中科院分区：

其他

文献类型：

作者：

V. Graziano;Andreas Dannhorn;Heather Hulme;K. Williamson;Hannah Buckley;Saadia A. Karim;Sheng Y. Lee;B. P. Kaistha;Sabita Islam;James E. D. Thaventhiran;F. Richards;R. Goodwin;R. Brais;J. Morton;S. Dovedi;A. Schuller;J. Eyles;D. Jodrell

胰腺导管腺癌（PDAC）患者的预后仍然极差。已经表明，腺苷途径有助于PDAC通过产生细胞外腺苷（eAdo）来逃避免疫系统及其对免疫疗法（免疫肿瘤疗法，IOT）的抗性的能力。在具有差异免疫浸润和对IOT的反应的同基因小鼠中使用PDAC的基因工程同种异体移植物模型，我们显示了腺苷途径在肿瘤浸润免疫细胞（特别是骨髓细胞群）中的富集。使用MS成像，我们发现细胞外腺苷分布在肿瘤中是不均匀的，在坏死区域周围的缺氧边缘具有高浓度，与丰富的骨髓浸润相关，使用成像质量细胞计数法（IMC）证明。促肿瘤发生M2巨噬细胞表达高水平的Adora 2a受体;特别是在IOT抗性模型中。使用抗-CD 73抗体和Adora 2a抑制剂的组合阻断eAdo（Adi）的体内形成和功能减缓了肿瘤生长并降低了转移负荷。此外，阻断腺苷途径可以提高细胞毒性药物或免疫疗法组合的疗效。最后，M2巨噬细胞和TME的浸润减少证明，TME重塑了肿瘤微环境（TME）。RNAseq分析显示，与免疫调节、缺氧和肿瘤基质相关的基因在PDAC后下调，并且由此衍生的特异性腺苷特征与PDAC患者的预后较差相关。eAdo的形成似乎促进了PDAC中免疫抑制性TME的发展，有助于其对常规和新型疗法的抗性。因此，腺苷途径的抑制可能代表了一种调节基质和改善PDAC患者治疗反应的策略。

The prognosis for patients with pancreatic ductal adenocarcinoma (PDAC) remains extremely poor. It has been suggested that the adenosine pathway contributes to the ability of PDAC to evade the immune system and its resistance to immunotherapies (Immuno-Oncology Therapy, IOT), by generating extracellular adenosine (eAdo). Using genetically engineered allograft models of PDAC in syngeneic mice with differential immune infiltration and response to IOT, we showed enrichment of the adenosine pathway in tumour-infiltrating immune cells (in particular, myeloid populations). Using MS-Imaging, we showed that extracellular adenosine distribution is heterogeneous in tumours, with high concentrations in hypoxic margins that surround necrotic areas, associated with a rich myeloid infiltration, demonstrated using Imaging Mass Cytometry (IMC). Pro-tumorigenic M2 macrophages express high levels of the Adora2a receptor; particularly in the IOT resistant model. Blocking the in vivo formation and function of eAdo (Adoi), using a combination of anti-CD73 antibody and an Adora2a inhibitor slowed tumour growth and reduced metastatic burden. In addition, blocking the adenosine pathway improved the efficacy of combinations of cytotoxic agents or immunotherapy. Finally, Adoi remodelled the tumour microenvironment (TME), as evidenced by reduced infiltration of M2 macrophages and Tregs. RNAseq analysis showed that genes related to immune modulation, hypoxia and tumour stroma were downregulated following Adoi and a specific adenosine signature derived from this is associated with a poorer prognosis in patients with PDAC. The formation of eAdo appears to promote the development of the immunosuppressive TME in PDAC, contributing to its resistance to conventional and novel therapies. Therefore, inhibition of the adenosine pathway may represent a strategy to modulate the stroma and improve therapy response in patients with PDAC.

Defining the spatial distribution of extracellular adenosine revealed a myeloid-dependent immunosuppressive microenvironment in pancreatic ductal adenocarcinoma

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