肿瘤细胞治疗研究
英文原题：Autocrine and paracrine LIF signals to collaborate sorafenib-resistance in hepatocellular carcinoma and effects of Kanglaite Injection.
Autocrine and paracrine LIF signals to collaborate sorafenib-resistance in hepatocellular carcinoma and effects of Kanglaite Injection.
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我们的研究结果验证了在 SFN 耐药中靶向 LIF 的治疗效果，揭示了对 SFN 敏感性增加的潜在机制，并试图阐明该干预如何可能有助于克服 SFN 耐药。
索拉非尼（SFN）是晚期肝细胞癌（HCC）的一线药物，但索拉非尼耐药是影响疗效的主要挑战，其机制尚未完全阐明。
研究白血病抑制因子（LIF）调节索拉非尼耐药微环境的治疗潜力及作用机制，以及康莱特注射液（KLTI）改善HCC索拉非尼耐药的作用，并为未来HCC联合用药研究提供方向。
使用已建立的索拉非尼耐药HCC细胞系，研究HCC肿瘤微环境（TME）中耐药与免疫抑制的关系。体内通过氯膦酸脂质体（CL）及抗NK1.1抗体耗竭巨噬细胞和自然杀伤（NK）细胞。体外采用多细胞共培养系统，检测KLTI对索拉非尼耐药的影响。进一步通过流式细胞术、qRT-PCR、蛋白质印迹及免疫组化进行机制分析。
肿瘤相关巨噬细胞（TAM）和NK细胞介导了小鼠HCC的索拉非尼耐药。在索拉非尼耐药状态下，M2样TAM旁分泌的LIF增加，并强烈抑制NK细胞增殖和细胞毒性，最终导致NK细胞耗竭及HCC转移恶化。与此同时，索拉非尼耐药使肿瘤细胞自分泌LIF增加，进一步促进保护性自噬并激活PI3K/Akt/mTOR获得性耐药通路。KLTI通过调节LIF及巨噬细胞-NK细胞相互作用，改善肿瘤免疫微环境（TIME）耐药状态，并提高HCC对索拉非尼的敏感性。
研究证实靶向LIF对索拉非尼耐药具有治疗作用，揭示提高索拉非尼敏感性的潜在机制，并探讨该干预如何帮助克服索拉非尼耐药。KLTI是一种有前景的免疫调节药物，可调节LIF及巨噬细胞-NK细胞相互作用，可能成为HCC治疗的联合用药选择。
Sorafenib (SFN) is the first-line medicine for advanced hepatocellular carcinoma (HCC). However, Sorafenib resistance is a main challenge of therapeutic efficacy, and the mechanisms have not been fully clarified.
The purpose of this study was to investigate the therapeutic potential and mechanism of action of LIF in modulating the microenvironment of SFN resistance as well as Kanglaite Injection (KLTI) in ameliorating SFN resistance in HCC and to guide future research directions for drug combination for HCC.
Established SFN-resistance HCC cell line was used to study the relationship between resistance and immunosuppression in HCC-tumor microenvironment (TME). In vivo macrophage and natural killer (NK) cells depletion were achieved by clodronate liposomes (CL) and anti-NK1.1. In vitro multiple cell co-culture systems were used to determine the effects of KLTI on SFN-resistant. Likewise, flow cytometry, qRT-PCR, Western blot, and immunohistochemistry analysis were performed for further mechanistic investigation.
Tumor associated-macrophages (TAMs) and NK cells mediated SFN-resistance in murine HCC. In the case of SFN resistance, the paracrine-leukemia inhibitory factor (LIF) by M2-like TAMs increased and potently suppressed NK cells proliferation and cytotoxicity, which finally inducing NK cells exhaustion and malignancy of HCC metastasis. Meanwhile, SFN resistance led to the increased autocrine-LIF of tumor cells, and further promoted the protective autophagy and activation of the acquired drug-resistant pathway PI3K/Akt/mTOR. KLTI could ameliorate the resistance of tumor immune microenvironment (TIME) and enhance the sensitivity of HCC to SFN by regulating LIF and macrophage-NK cell interaction.
Our findings verify the therapeutic effects of targeting LIF in SFN-resistance, uncover the potential mechanism for the increased sensitivity to SFN and sought to elucidate how this intervention might contribute to overcoming SFN resistance. KLTI is a promising immunomodulatory drug by regulating LIF and macrophage-NK cell interaction, which could be a potential combination partner for HCC treatment.
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