Immunoregulatory cyclophilin a improves low-dose chemotherapy with a modulation of the immune tumor microenvironment in experimental models of melanoma B16 and lymphoma EL4 in vivo.

IF 2.7 4区 医学 Q3 ONCOLOGY Cancer Chemotherapy and Pharmacology Pub Date : 2024-09-01 Epub Date: 2024-06-24 DOI:10.1007/s00280-024-04691-3
Anastasiia A Kalinina, Leila R Tilova, Dmitry B Kazansky, Ludmila M Khromykh
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Abstract

Purpose: Different regimens of low-dose chemotherapy (LDC) are currently being actively developed and introduced into clinical practice. Along with its obvious advantages compared to conventional chemotherapy (low toxicity, prevention of drug resistance), LDC could also stimulate anti-tumor immune responses in a patient by activating effectors of innate and adaptive immunity and diminishing tumor-associated immunosuppression. As non-myeloablative, LDC could be successfully combined with different anti-cancer immunotherapeutic strategies, including immunoregulatory cytokines. Secreted cyclophilin A (CypA) is of particular interest in this respect. Previously, we showed that recombinant human CypA (rhCypA) had pleiotropic immunostimulatory activity and anti-tumor effects. Thus, rhCypA could be potentially proposed as a perspective component of combined therapy with LDC.

Methods: In this work, we evaluated the anti-tumor effects of rhCypA combined with low doses of cyclophosphamide, doxorubicin, dacarbazine, and paclitaxel in the experimental mouse tumor models of melanoma B16 and lymphoma EL4 in vivo.

Results: Synergic and potentiating effects of rhCypA combined with LDC were shown in these studies. Furthermore, as a monotherapeutic agent and a component of combined chemoimmunotherapy, rhCypA was shown to modulate the immune tumor microenvironment by enhancing tumor infiltration with macrophages, NK cells, and T cells. It was also found that rhCypA stimulated both systemic and local anti-tumor immune responses.

Conclusion: RhCypA could be potentially proposed as a perspective component of the combined cancer chemoimmunotherapy.

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在体内黑色素瘤 B16 和淋巴瘤 EL4 的实验模型中,免疫调节环嗜蛋白 a 可通过调节免疫肿瘤微环境来改善低剂量化疗。
目的:目前正在积极开发不同的低剂量化疗(LDC)方案,并将其引入临床实践。与传统化疗相比,低剂量化疗具有明显的优势(低毒性、防止耐药性),还能通过激活先天性免疫和适应性免疫的效应因子,减轻肿瘤相关的免疫抑制,从而激发患者的抗肿瘤免疫反应。由于不产生瘤细胞,LDC 可以成功地与不同的抗癌免疫治疗策略(包括免疫调节细胞因子)相结合。在这方面,分泌型环嗜蛋白 A(CypA)尤其值得关注。此前,我们曾发现重组人 CypA(rhCypA)具有多向性免疫刺激活性和抗肿瘤作用。因此,rhCypA 有可能成为 LDC 联合疗法的一个重要组成部分:在这项工作中,我们评估了 rhCypA 与低剂量环磷酰胺、多柔比星、达卡巴嗪和紫杉醇联合使用对小鼠黑色素瘤 B16 和淋巴瘤 EL4 模型的抗肿瘤作用:结果:在这些研究中,rhCypA 与 LDC 联用产生了协同和增效作用。此外,rhCypA 作为单一治疗剂和联合化疗免疫疗法的组成部分,可通过增强巨噬细胞、NK 细胞和 T 细胞对肿瘤的浸润来调节免疫肿瘤微环境。研究还发现,rhCypA 可刺激全身和局部的抗肿瘤免疫反应:结论:RhCypA 有可能成为癌症化疗免疫疗法的一个重要组成部分。
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来源期刊
CiteScore
6.10
自引率
3.30%
发文量
116
审稿时长
2.5 months
期刊介绍: Addressing a wide range of pharmacologic and oncologic concerns on both experimental and clinical levels, Cancer Chemotherapy and Pharmacology is an eminent journal in the field. The primary focus in this rapid publication medium is on new anticancer agents, their experimental screening, preclinical toxicology and pharmacology, single and combined drug administration modalities, and clinical phase I, II and III trials. It is essential reading for pharmacologists and oncologists giving results recorded in the following areas: clinical toxicology, pharmacokinetics, pharmacodynamics, drug interactions, and indications for chemotherapy in cancer treatment strategy.
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