Defining the spatial distribution of extracellular adenosine revealed a myeloid-dependent immunosuppressive microenvironment in pancreatic ductal adenocarcinoma.
Defining the spatial distribution of extracellular adenosine revealed a myeloid-dependent immunosuppressive microenvironment in pancreatic ductal adenocarcinoma.
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DOI：
10.1136/jitc-2022-006457
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发表时间：
2023-08
影响因子：
10.9
通讯作者：
中科院分区：
文献类型：
--
作者：
胰腺导管腺癌（PDAC）患者的预后仍然非常差。有研究表明，腺苷途径有助于PDAC逃避免疫系统的能力，从而通过产生细胞外腺苷（eAdo）来抵抗免疫肿瘤治疗（IOT）。利用PDAC基因工程同种异体移植模型，研究了腺苷途径对PDAC肿瘤微环境（TME）的影响。PDAC同种异体移植模型具有明确的和不同的免疫浸润以及对物联网和KPC小鼠自体肿瘤的反应。采用流式细胞术和成像质细胞术（IMC）表征肿瘤浸润免疫细胞的亚群频率和空间分布。质谱成像（MSI）用于观察PDAC肿瘤中的腺苷区室化。RNA测序用于评估腺苷途径对免疫环境形成的影响，并将我们的发现与人类PDAC的已发表数据集联系起来。我们在小鼠模型中证实了腺苷途径组分在肿瘤浸润免疫细胞（特别是髓系细胞）中的高表达。MSI显示细胞外腺苷在肿瘤中的分布是不均匀的，在坏死周围、缺氧区域有高浓度，与丰富的髓细胞浸润相关，IMC证实了这一点。致瘤蛋白M2巨噬细胞高水平表达Adora2a受体；特别是在物联网抵抗模型中。使用抗cd73抗体和Adora2a抑制剂的组合阻断eAdo （Adoi）在体内的形成和功能，可减缓肿瘤生长并减少转移负担。此外，阻断腺苷途径可提高细胞毒性药物或免疫治疗联合治疗的疗效。Adoi通过减少M2巨噬细胞和调节性T细胞的浸润来重塑TME。RNA测序分析显示，Adoi治疗后，与免疫调节、缺氧和肿瘤基质相关的基因下调，由此产生的特异性腺苷特征与PDAC患者较差的预后相关。eAdo的形成促进了PDAC中免疫抑制TME的发展，有助于其对传统和新疗法的抵抗。因此，抑制腺苷途径可能是调节PDAC免疫环境和改善PDAC患者治疗反应的一种策略。
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 hence, its resistance to immuno-oncology therapies (IOT), by generating extracellular adenosine (eAdo). Using genetically engineered allograft models of PDAC in syngeneic mice with defined and different immune infiltration and response to IOT and autochthonous tumors in KPC mice we investigated the impact of the adenosine pathway on the PDAC tumor microenvironment (TME). Flow cytometry and imaging mass cytometry (IMC) were used to characterize the subpopulation frequency and spatial distribution of tumor-infiltrating immune cells. Mass spectrometry imaging (MSI) was used to visualize adenosine compartmentalization in the PDAC tumors. RNA sequencing was used to evaluate the influence of the adenosine pathway on the shaping of the immune milieu and correlate our findings to published data sets in human PDAC. We demonstrated high expression of adenosine pathway components in tumor-infiltrating immune cells (particularly myeloid populations) in the murine models. MSI demonstrated that extracellular adenosine distribution is heterogeneous in tumors, with high concentrations in peri-necrotic, hypoxic regions, associated with rich myeloid infiltration, demonstrated using IMC. Protumorigenic 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 tumor growth and reduced metastatic burden. Additionally, blocking the adenosine pathway improved the efficacy of combinations of cytotoxic agents or immunotherapy. Adoi remodeled the TME, by reducing the infiltration of M2 macrophages and regulatory T cells. RNA sequencing analysis showed that genes related to immune modulation, hypoxia and tumor 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 promotes 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 PDAC immune milieu and improve therapy response in patients with PDAC.
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影响因子：
8.8
作者：
Ino Y;Yamazaki-Itoh R;Shimada K;Iwasaki M;Kosuge T;Kanai Y;Hiraoka N
通讯作者：
Hiraoka N
影响因子：
10.1
作者：
通讯作者：
--
DOI：
10.1158/1078-0432.ccr-17-3099
发表时间：
2018-03-15
期刊：
Clinical cancer research : an official journal of the American Association for Cancer Research
影响因子：
--
作者：
Hu ZI;Shia J;Stadler ZK;Varghese AM;Capanu M;Salo-Mullen E;Lowery MA;Diaz LA Jr;Mandelker D;Yu KH;Zervoudakis A;Kelsen DP;Iacobuzio-Donahue CA;Klimstra DS;Saltz LB;Sahin IH;O'Reilly EM
通讯作者：
O'Reilly EM
影响因子：
8.8
作者：
通讯作者：
--
影响因子：
8.8
作者：
Candido JB;Morton JP;Bailey P;Campbell AD;Karim SA;Jamieson T;Lapienyte L;Gopinathan A;Clark W;McGhee EJ;Wang J;Escorcio-Correia M;Zollinger R;Roshani R;Drew L;Rishi L;Arkell R;Evans TRJ;Nixon C;Jodrell DI;Wilkinson RW;Biankin AV;Barry ST;Balkwill FR;Sansom OJ
通讯作者：
Sansom OJ