Oncolytic avian reovirus-sensitized tumor infiltrating CD8⁺ T cells triggering immunogenic apoptosis in gastric cancer.

IF 8.2 2区生物学 Q1 CELL BIOLOGY Cell Communication and Signaling Pub Date : 2024-10-21 DOI:10.1186/s12964-024-01888-0

Yi-Ying Wu, Feng-Hsu Wu, I-Chun Chen, Tsai-Ling Liao, Muhammad Munir, Hung-Jen Liu

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Abstract

Background: Gastric cancer (GC) is a leading malignant disease in numerous countries, including Taiwan with limited therapeutic options. Animal viruses including oncolytic avian reovirus (ARV) have the possibility to avoid pre-existing immunity in humans, while being safe and immunostimulatory. Here, we provide a novel insight into oncolytic ARV and UV-ARV-sensitized patient's peripheral blood mononuclear cells (P-PBMCs) and tumor infiltrating lymphocytes (TILs) killing primary GC (PGC) cells through the surface TLR3 and TRAIL/DR4/DR5 immunogenic apoptosis pathway.

Methods: We conducted a comprehensive study to reveal whether ARV- or UV-inactivated ARV (UV-ARV)-modulated P-PBMCs or TILs killing ARV- and UV-ARV-sensitized AGS cells and PGC cells derived from clinical patients and to investigate the regulation of surface TLR3 receptor and upstream signaling pathways. Apoptosis analysis by flow cytometry and Western blot, suppression of signal pathway by specific inhibitors, in situ proximity ligation assay (PLA), time-resolved flurometry and lactate dehydrogenase (LDH) cytotoxicity assays, and an in vitro co-culture model were established to study the interplay between ARV- and UV-ARV-sensitized P-PBMCs and TILs to kill PGC cells and their upstream pathways.

Results: Our results reveal that increased levels of DR4 and DR5 were observed in ARV and UV-ARV sensitized PGC cells through the TLR3/p38/p53 signaling pathway. Importantly, we found that the σC protein of ARV or UV-ARV interacted with surface TLR3 of CD8⁺ TILs, thereby triggering the TLR3/NF-κB/IFN-γ/TRAIL signaling pathway which induces immunogenic apoptosis of PGC cells. This study sheds further light on the molecular basis behind ARV oncolysis and facilitates the ARV or UV-ARV as a cancer therapeutic.

Conclusions: The study provides novel insights into ARV- or UV-ARV-sensitized P-PBMCs and CD8⁺ TILs to kill PGC cells through the immunogenic apoptosis pathway. We conclude that P-PBMCs can easily be obtained from GC patients and provide a rich source as TILs to kill PGC cells.

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肿瘤溶解性禽再病毒致敏的肿瘤浸润性 CD8+ T 细胞引发胃癌免疫性凋亡。

背景胃癌（GC）是包括台湾在内的许多国家的主要恶性疾病，但治疗方案有限。包括溶瘤禽再病毒（ARV）在内的动物病毒可以避免人类原有的免疫力，同时具有安全性和免疫刺激作用。在此，我们对溶瘤ARV和UV-ARV致敏的患者外周血单核细胞（P-PBMCs）和肿瘤浸润淋巴细胞（TILs）通过表面TLR3和TRAIL/DR4/DR5免疫原性凋亡途径杀死原发性GC（PGC）细胞进行了新的深入研究：我们进行了一项综合研究，以揭示ARV或UV灭活ARV（UV-ARV）调控的P-PBMCs或TILs是否杀伤ARV和UV-ARV致敏的AGS细胞和来自临床患者的PGC细胞，并研究表面TLR3受体和上游信号通路的调控。通过流式细胞术和Western印迹进行细胞凋亡分析、用特异性抑制剂抑制信号通路、原位近接试验（PLA）、时间分辨荧光测定法和乳酸脱氢酶（LDH）细胞毒性试验以及体外共培养模型，研究了ARV和UV-ARV致敏的P-PBMCs和TILs杀死PGC细胞的相互作用及其上游通路：结果：我们的研究结果表明，通过TLR3/p38/p53信号通路，在ARV和UV-ARV致敏的PGC细胞中观察到DR4和DR5水平升高。重要的是，我们发现 ARV 或 UV-ARV 的 σC 蛋白与 CD8+ TILs 表面的 TLR3 相互作用，从而触发 TLR3/NF-κB/IFN-γ/TRAIL 信号通路，诱导 PGC 细胞免疫性凋亡。这项研究进一步揭示了ARV溶瘤背后的分子基础，有助于将ARV或UV-ARV作为癌症疗法：本研究为ARV或UV-ARV致敏的P-PBMCs和CD8+ TILs通过免疫原性凋亡途径杀死PGC细胞提供了新的见解。我们得出的结论是，P-PBMCs 可以很容易地从 GC 患者身上获得，并为 TILs 提供了丰富的来源，从而杀死 PGC 细胞。

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来源期刊

Cell Communication and Signaling CELL BIOLOGY-

CiteScore

11.00

自引率

0.00%

发文量

180

期刊介绍： Cell Communication and Signaling (CCS) is a peer-reviewed, open-access scientific journal that focuses on cellular signaling pathways in both normal and pathological conditions. It publishes original research, reviews, and commentaries, welcoming studies that utilize molecular, morphological, biochemical, structural, and cell biology approaches. CCS also encourages interdisciplinary work and innovative models, including in silico, in vitro, and in vivo approaches, to facilitate investigations of cell signaling pathways, networks, and behavior. Starting from January 2019, CCS is proud to announce its affiliation with the International Cell Death Society. The journal now encourages submissions covering all aspects of cell death, including apoptotic and non-apoptotic mechanisms, cell death in model systems, autophagy, clearance of dying cells, and the immunological and pathological consequences of dying cells in the tissue microenvironment.