唾液腺腺样囊性癌细胞的假正常形态破坏了免疫细胞的抗肿瘤反应性：以肿瘤细胞为基础的免疫回避机制

IF 1.5 Q4 ONCOLOGY Cancer reports Pub Date : 2024-09-26 DOI:10.1002/cnr2.70019

Rajdeep Chakraborty, Thiri Zaw, Pallavi Khodlan, Charbel Darido, Giuseppe Palmisano, Arthur Chien, Aidan Tay, Shoba Ranganathan, Fei Liu

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摘要

导言唾液腺腺样囊性癌（ACC）、粘液表皮样癌（MEC）和口腔鳞状细胞癌（OSCC）多发于头颈部。迄今为止，免疫检查点抑制剂对 ACC 的治疗均告失败。Gipie（CCDC88B）是一种能激活免疫细胞的微管连接蛋白。我们在头颈癌细胞中发现了 Gipie 的表达。我们假设 Gipie 的存在会降低免疫细胞对头颈癌的抗肿瘤反应性。为了确定 Gipie 对口腔癌和唾液腺癌细胞的影响，我们在癌症-免疫细胞共培养模型中沉默了癌细胞中的 Gipie，并进行了三维 Z 系列共聚焦成像、附件素 V 和免疫激活流式细胞术、蛋白质组分析仪和发现期蛋白质组学研究。结果 ACC 细胞在免疫共培养模型中形成了假正常形态。在 ACC 细胞中沉默 Gipie 后，凋亡细胞和活化的自然杀伤细胞显著增加，调节性 T 细胞减少。其他唾液腺癌和口腔癌细胞对 Gipie 的影响微乎其微。蛋白质组分析仪和蛋白质组学检测证实，Gipie 会影响 ACC 免疫共培养模型中的增殖机制和免疫激活蛋白。结论总体而言，我们得出结论，Gipie 的存在在 ACC 与免疫细胞相互作用过程中起到了干扰作用。

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Pseudonormal Morphology of Salivary Gland Adenoid Cystic Carcinoma Cells Subverts the Antitumor Reactivity of Immune Cells: A Tumour-Cell–Based Initiation of Immune Evasion

Introduction

Salivary gland adenoid cystic carcinoma (ACC), mucoepidermoid carcinoma (MEC) and oral squamous cell carcinoma (OSCC) occurs within the head and neck region. So far immune check point inhibitors failed in ACC. Gipie (CCDC88B) is a microtubule linker protein that activates immune cells. Gipie expressions found in head and neck cancer cells. We hypothesised that the presence of Gipie diminishes anti-tumour reactivity of immune cells towards head and neck cancer.

Method

To determine the effect of Gipie in oral and salivary gland cancer cells, Gipie was silenced in cancer cells in cancer-immune cells co-culture models and we performed 3D Z series confocal imaging, annexin V and immune activation flow cytometry, proteome profiler and discovery phase proteomics.

Results

ACC cells morphed into pseudonormal morphology in immune co-culture models. Silencing Gipie in ACC cells showed significant increase of apoptotic cells and activated natural killer cells, and lowering of regulatory T cells. Other salivary and oral cancer cells showed negligible effect of Gipie. Proteome profiler and proteomics assay confirmed Gipie affecting proliferation mechanism and immune activated proteins in ACC immune co-culture models.