A detoxified TLR4 agonist inhibits tumour growth and lung metastasis of osteosarcoma by promoting CD8+ cytotoxic lymphocyte infiltration.

BJC reports Pub Date : 2025-01-27 DOI:10.1038/s44276-024-00120-3

Ryunosuke Oyama, Akira Nabeshima, Makoto Endo, Alexey Novikov, Toshifumi Fujiwara, Capucine Phelip, Nobuhiko Yokoyama, Yoshinao Oda, Martine Caroff, Yoshihiro Matsumoto, Jerome Kerzerho, Yasuharu Nakashima

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Abstract

Background: Osteosarcoma is the most common malignant bone tumour with limited treatment options and poor outcomes in advanced metastatic cases. Current immunotherapies show limited efficacy, highlighting the need for novel therapeutic approaches. Systemic immune activation by Toll-like receptor 4 (TLR4) immunostimulants has shown great promise; however, current TLR4 agonists' toxicity hinders this systemic approach in patients with osteosarcoma.

Methods: We compared the antitumour effect of lipopolysaccharides (LPS) with that of an innovative chemically detoxified TLR4 agonist (Lipo-MP-LPS) in a syngeneic metastatic osteosarcoma mouse model. Lipo-MP-LPS exhibited an optimal safety and solubility profile for systemic administration at an effective dose. We evaluated tumour growth, lung metastases, and immune cell infiltration in wild-type and TLR4-mutant mice and performed selective immunodepletion.

Results: Lipo-MP-LPS exhibited antitumour effects against localised osteosarcoma tumours and lung metastases, like those of natural LPS. Lipo-MP-LPS promoted CD8⁺ T cells and M1 macrophages infiltration in primary tumours and CD8⁺ T cells in metastases, with an M1-phenotype macrophage shift. The Lipo-MP-LPS antitumour effects were found to depend on TLR4 and CD8⁺ T cells, but not on macrophages.

Conclusion: Lipo-MP-LPS inhibited tumour growth and lung metastasis of osteosarcoma by promoting CD8 + T cell infiltration, indicating its therapeutic potential for advanced osteosarcoma.

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一种解毒的TLR4激动剂通过促进CD8+细胞毒性淋巴细胞浸润抑制骨肉瘤的肿瘤生长和肺转移。

背景：骨肉瘤是最常见的恶性骨肿瘤，治疗方案有限，晚期转移病例预后差。目前的免疫疗法显示有限的疗效，强调需要新的治疗方法。toll样受体4 （TLR4）免疫刺激剂的全身免疫激活显示出很大的前景；然而，目前TLR4激动剂的毒性阻碍了骨肉瘤患者的全身治疗。方法：我们在同基因转移性骨肉瘤小鼠模型中比较了脂多糖（LPS）和一种创新的化学解毒TLR4激动剂（脂多糖- mp -LPS）的抗肿瘤作用。lipop - mp - lps在有效剂量下具有最佳的安全性和溶解度。我们评估了野生型和tlr4突变小鼠的肿瘤生长、肺转移和免疫细胞浸润，并进行了选择性免疫消耗。结果：脂多糖对局部骨肉瘤肿瘤和肺转移瘤表现出与天然脂多糖相似的抗肿瘤作用。脂质体- mp - lps促进原发肿瘤中CD8+ T细胞和M1巨噬细胞浸润，促进转移瘤中CD8+ T细胞浸润，使巨噬细胞向M1表型转移。lipop - mp - lps的抗肿瘤作用依赖于TLR4和CD8+ T细胞，而不依赖于巨噬细胞。结论：脂多糖（lipop - mp - lps）通过促进CD8 + T细胞浸润抑制骨肉瘤肿瘤生长和肺转移，提示其治疗晚期骨肉瘤的潜力。

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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