肿瘤细胞治疗研究
英文原题：An ICOSL-armed oncolytic adenovirus activates CD4(+) T cell to potentiate antitumor immunity and synergizes with anti-PD-1 or CAR-T cell therapy in colorectal cancer.
An ICOSL-armed oncolytic adenovirus activates CD4(+) T cell to potentiate antitumor immunity and synergizes with anti-PD-1 or CAR-T cell therapy in colorectal cancer.
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我们的研究不仅揭示了常规溶瘤腺病毒疗效欠佳与 ICOSL 下调及 CD4⁺ T 细胞辅助功能受损相关，还成功开发了 ADV-ICOSL 以逆转这一局限。
溶瘤腺病毒（ADV）治疗结直肠癌（CRC）的疗效受限于其无法在肿瘤微环境（TME）中有效扩增CD4+ T细胞。本研究旨在阐明其机制，并通过病毒工程克服这一瓶颈。
我们以ADV-NC为骨架，构建表达诱导型T细胞共刺激配体ICOSL的溶瘤腺病毒ADV-ICOSL。在MC38和CT26小鼠CRC模型中系统评估其抗肿瘤疗效、安全性及诱导免疫记忆的能力。采用流式细胞术、共培养实验、RNA测序和特异性通路抑制剂研究作用机制，并评估其与抗PD-1或CAR-T 细胞疗法的协同潜力。此外，我们开发了人源化ICOSL表达病毒ADV-hICOSL，并在细胞系来源异种移植（CDX）和患者来源异种移植（PDX）模型中进行验证。
我们首先发现，ADV-NC治疗会降低TME中的ICOSL水平，导致CD4+ T细胞共刺激不足。相比之下，ADV-ICOSL显著提高ICOSL表达，抗肿瘤疗效更佳，并能够诱导长期免疫记忆。机制研究显示，ADV-ICOSL通过提高ICOSL水平，激活CD4+ T细胞中的PI3K/Akt-NF-κB信号轴，促进其分泌IL-2。IL-2以非接触依赖方式强效增强CD8+ T细胞增殖和细胞毒性，该过程严格依赖CD4+ T细胞。ADV-ICOSL与抗PD-1或CAR-T 治疗联合时均表现出显著协同作用。值得注意的是，ADV-hICOSL可有效增加CDX/PDX模型中CD4+ T细胞和GZMB+ CD8+ T细胞浸润，并产生强效抗肿瘤作用。
本研究不仅揭示，传统溶瘤腺病毒疗效不佳与ICOSL下调及CD4+ T细胞辅助功能受损相关，还成功开发了可逆转这一局限的ADV-ICOSL。本研究为CRC溶瘤病毒治疗提供了新的联合策略和坚实的实验依据。
The efficacy of oncolytic adenoviruses (ADVs) in colorectal cancer (CRC) is limited by their inability to effectively expand CD4 + T cells within the tumor microenvironment (TME). This study aimed to elucidate the underlying mechanism and overcome this bottleneck through viral engineering.
We constructed an oncolytic adenovirus expressing inducible T cell co-stimulator ligand (ICOSL), designated ADV-ICOSL, based on the backbone virus ADV-NC. Its antitumor efficacy, safety, and ability to induce immunological memory were systematically evaluated in MC38 and CT26 murine colorectal cancer (CRC) models. The mechanism of action was investigated using flow cytometry, co-culture assays, RNA sequencing, and specific pathway inhibitors. The synergistic potential with anti-PD-1 or chimeric antigen receptor T cell (CAR-T) therapy was assessed. Furthermore, a humanized ICOSL-expressing virus (ADV-hICOSL) was developed and validated in cell line-derived xenograft (CDX) and patient-derived xenograft (PDX) models.
We initially discovered that ADV-NC treatment led to decreased ICOSL levels in the TME, resulting in insufficient co-stimulation for CD4 + T cells. In contrast, ADV-ICOSL significantly elevated ICOSL expression and demonstrated superior antitumor efficacy and the capacity to induce long-term immune memory. Mechanistic studies revealed that ADV-ICOSL, via elevating ICOSL, activated the PI3K/Akt-NF- B signaling axis in CD4 + T cells, promoting their secretion of IL-2. IL-2, in a non-contact-dependent manner, potently enhanced the proliferation and cytotoxicity of CD8 + T cells. This process was strictly dependent on CD4 + T cells. Furthermore, ADV-ICOSL exhibited significant synergistic effects when combined with either anti-PD-1 or CAR-T therapy. Importantly, ADV-hICOSL effectively increased the infiltration of CD4 + T and GZMB + CD8 + T cells in CDX/PDX models, exerting potent antitumor effects.
Our study not only reveals that the suboptimal efficacy of conventional oncolytic adenovirus is associated with ICOSL downregulation and impaired CD4 + T cell help, but also successfully develops ADV-ICOSL to reverse this limitation. This study provides a novel combinatorial strategy and a solid experimental foundation for oncolytic virotherapy in CRC.
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