Enhanced potency of immune checkpoint inhibitors against poorly immunological solid tumors by immune stimulatory oncolytic adenoviruses-mediated remodeling of the tumor microenvironment.

IF 6 2区医学 Q1 BIOCHEMISTRY & MOLECULAR BIOLOGY

Molecular Medicine Pub Date : 2025-05-07 DOI:10.1186/s10020-025-01223-4

Hyo Min Ahn, Bo-Kyeong Jung, JinWoo Hong, Dayoung Hong, A-Rum Yoon, Chae-Ok Yun

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引用次数: 0

Abstract

Immune checkpoint inhibitor (ICI) have shown promising results against a variety of solid tumors across clinical trials. However, ICI monotherapy is often ineffective in patients with non-immunogenic tumors that exhibit high level of immunosuppression and low level of tumor infiltrating lymphocytes. To address these limitations, we have investigated a combination of ICIs [anti-PD-1 antibody (αPD-1), anti-PD-L1 antibody (αPD-L1), or anti-CTLA-4 antibody (αCTLA-4)] with several different immune stimulatory oncolytic adenoviruses (Ads) expressing different combinations of antitumor cytokines or immune modulatory factors [e.g., (1) interleukin (IL)-12 and granulocyte-macrophage colony-stimulating factor (GM-CSF; RdB/IL12/GMCSF), (2) IL-12 and short hairpin ribonucleic acid (shRNA) targeting vascular endothelial growth factor (RdB/IL12/shVEGF), (3) IL-12 and decorin (RdB/IL12/DCN), (4) GM-CSF, and thymidine kinase (RdB/IL12/GMCSF-TK), or (5) IL-12, GM-CSF, and relaxin (RdB/IL12/GMCSF-RLX)] to overcome tumor-induced immunosuppression. Through comparative evaluation of combination therapy regimens, our findings have identified αPD-1 as the optimal ICI candidate to synergize with different oncolytic Ads to induce potent antitumor immune response against poorly immunological solid tumors.

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通过免疫刺激溶瘤腺病毒介导的肿瘤微环境重塑，增强免疫检查点抑制剂对抗低免疫实体瘤的效力。

免疫检查点抑制剂（ICI）在各种实体瘤的临床试验中显示出良好的效果。然而，ICI单药治疗对于表现出高水平免疫抑制和低水平肿瘤浸润淋巴细胞的非免疫原性肿瘤患者往往无效。为了解决这些局限性，我们研究了ICIs[抗pd -1抗体（αPD-1），抗pd - l1抗体（αPD-L1）或抗ctla -4抗体（αCTLA-4）]与几种不同的免疫刺激溶瘤腺病毒（Ads）的组合，这些病毒表达不同的抗肿瘤细胞因子或免疫调节因子[例如，(1)白细胞介素(IL)-12和粒细胞-巨噬细胞集群刺激因子（GM-CSF）；RdB/IL12/GMCSF), (2) IL-12和短发卡核糖核酸（shRNA）靶向血管内皮生长因子（RdB/IL12/shVEGF）， (3) IL-12和decorin (RdB/IL12/DCN), (4) GM-CSF和胸苷激酶（RdB/IL12/GMCSF- tk），或(5)IL-12、GM-CSF和松弛素（RdB/IL12/GMCSF- rlx）来克服肿瘤诱导的免疫抑制。通过对联合治疗方案的比较评估，我们的研究结果确定αPD-1是最佳的ICI候选者，可以与不同的溶瘤性ad协同作用，诱导对免疫力低下的实体瘤产生有效的抗肿瘤免疫反应。

本文章由计算机程序翻译，如有差异，请以英文原文为准。

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来源期刊

Molecular Medicine 医学-生化与分子生物学

CiteScore

8.60

自引率

0.00%

发文量

137

审稿时长

1 months

期刊介绍： Molecular Medicine is an open access journal that focuses on publishing recent findings related to disease pathogenesis at the molecular or physiological level. These insights can potentially contribute to the development of specific tools for disease diagnosis, treatment, or prevention. The journal considers manuscripts that present material pertinent to the genetic, molecular, or cellular underpinnings of critical physiological or disease processes. Submissions to Molecular Medicine are expected to elucidate the broader implications of the research findings for human disease and medicine in a manner that is accessible to a wide audience.