Role of cell based approaches in cancer immunotherapy

Anjum Mahmood, A. Srivastava, S. Srivastava, P. Hiteshree, Ya., Neel Khokhani, D. Patel, Rangnath Mishra
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Abstract

An integrated immune system prevents development and progression of neoplastic cells in a process termed as immune surveillance. T-cells play an important role in detecting and eliminating tumor cells. In turn, they are dependent on dendritic cells for tumor antigen presentation and activation signals to stimulate them. One of the most important reasons behind failure of cancer immunosurveillance is hampered T-cell activity due to lack of co-stimulatory activation signals by dendritic cells resulting into peripheral tolerance. Other factors driving tumor progression include immunosuppressive tumor micro-environment, infiltration of regulatory T cells, release of immunosuppressive cytokines like IL-10 and TGF-β, reduced expression of MHC molecules, myeloid derived suppressor cells (MDSCs) and heterogeneity of tumor sub-clones at the genetic level. Studies have shown that expansion of Treg cells is associated with poor prognosis and reduced survival. Similarly, abnormal accumulation of MDSCs is also correlated with tumor evasion mechanism. Though, chemotherapy is first line of treatment, the efficacy is restricted later due to development of drug resistance. The major reasons for resistance development includes drug-targeted gene amplification (e.g. BRAF gene) and substitution mutation in some cancer cells leading to the escape of drug cytotoxic effect.1 Further, non-specific cytotoxicity of chemo agents result into lymphodepliton. To address all these issues, new therapeutic interventions are required which alone or in combination alter the tumor microenvironment to enhance beneficial effects without causing toxicity. In this context, immunotherapy is expected to play significant role. Cancer immunotherapy can be defined as set of techniques aimed to eliminate malignant tumors through mechanisms involving immune system responses. The agents driving immune alteration are termed as immunomodulators. In this review, we will discuss briefly some of specific methods mediating immunomodulation including dendritic cell based approaches, adoptive T cells transfer and mesenchymal stem cells based targeted delivery of drugs.
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基于细胞的方法在癌症免疫治疗中的作用
综合免疫系统在称为免疫监视的过程中阻止肿瘤细胞的发展和进展。t细胞在检测和清除肿瘤细胞中起着重要的作用。反过来,它们依赖树突状细胞提供肿瘤抗原和激活信号来刺激它们。肿瘤免疫监视失败的最重要原因之一是由于树突状细胞缺乏共刺激激活信号导致外周耐受而阻碍t细胞活性。其他驱动肿瘤进展的因素包括肿瘤微环境的免疫抑制性、调节性T细胞的浸润、IL-10、TGF-β等免疫抑制因子的释放、MHC分子、髓源性抑制细胞(myeloid derived suppressor cells, MDSCs)的表达减少以及肿瘤亚克隆在遗传水平上的异质性。研究表明,Treg细胞的扩增与预后不良和生存率降低有关。同样,MDSCs的异常积累也与肿瘤逃逸机制有关。虽然化疗是一线治疗,但由于耐药的发展,其疗效受到限制。耐药发生的主要原因包括药物靶向基因扩增(如BRAF基因)和部分癌细胞发生替代突变导致药物细胞毒性作用逃逸此外,化疗药物的非特异性细胞毒性导致淋巴部署。为了解决所有这些问题,需要新的治疗干预措施,单独或联合改变肿瘤微环境,以增强有益效果而不引起毒性。在此背景下,免疫治疗有望发挥重要作用。癌症免疫治疗可以定义为一套旨在通过涉及免疫系统反应的机制消除恶性肿瘤的技术。驱动免疫改变的因子被称为免疫调节剂。在这篇综述中,我们将简要讨论一些特定的介导免疫调节的方法,包括基于树突状细胞的方法,过继性T细胞转移和基于间充质干细胞的靶向药物递送。
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