Department of Surgical and Morphological Sciences, University of Insubria, Via Ottorino Rossi, n.9, 21100 Varese, Italy.
J Neuroimmune Pharmacol. 2013 Mar;8(1):28-36. doi: 10.1007/s11481-012-9423-7. Epub 2012 Dec 7.
A crucial parameter for activation of the anti-tumor immune response is an adequate antigen availability (AAA) defined here as the optimal tumor antigen dose and related antigen processing and MHC-II-restricted presentation necessary to efficiently trigger tumor-specific TH cells. We will discuss two distinct experimental systems: a) a preventive anti-tumor vaccination system; b) a therapy-induced anti-tumor vaccination approach. In the first case tumor cells are rendered constitutively MHC-II+ by transfecting them with the MHC-II transcriptional activator CIITA. Here AAA is generated by the function of tumor's newly expressed MHC-II molecules to present tumor-associated antigens to tumor-specific TH cells. In the second case, AAA is generated by treating established tumors with neovasculature-targeted TNFα. In conjuction with Melphalan, targeted TNFα delivery produces extensive areas of tumor necrosis that generate AAA capable of optimally activate tumor-specific TH cells which in turn activate CTL immune effectors. In both experimental systems tumor rejection and persistent and long-lived TH cell anti-tumor memory, responsible of defending the animals from subsequent challenges with tumor cells, are achieved. Based on these and other investigators' results we propose that AAA is a key element for triggering adaptive immune functions resulting in subversion from a pro-tumor to an anti-tumor microenvironment, tumor rejection and acquisition of anti-tumor immune memory. Hypotheses of neuro-immune networks involved in these approaches are discussed. These considerations are important also for the comprehension of how chemotherapy and/or radiation therapies may help to block and/or to eradicate the tumor and for the construction of suitable anti-tumor vaccine strategies.
激活抗肿瘤免疫反应的一个关键参数是充足的抗原可用性（AAA），这里定义为最佳肿瘤抗原剂量和相关的抗原处理以及 MHC-II 限制性呈递，这些是有效触发肿瘤特异性 TH 细胞所必需的。我们将讨论两个不同的实验系统：a）预防性抗肿瘤疫苗接种系统；b）治疗诱导的抗肿瘤疫苗接种方法。在第一种情况下，通过用 MHC-II 转录激活剂 CIITA 转染肿瘤细胞，使肿瘤细胞持续 MHC-II+。在这里，AAA 是通过肿瘤新表达的 MHC-II 分子的功能产生的，以将肿瘤相关抗原呈递给肿瘤特异性 TH 细胞。在第二种情况下，通过用靶向新血管生成的 TNFα 治疗已建立的肿瘤来产生 AAA。与美法仑联合使用，靶向 TNFα 递送会产生广泛的肿瘤坏死区域，从而产生能够最佳激活肿瘤特异性 TH 细胞的 AAA，而肿瘤特异性 TH 细胞又会激活 CTL 免疫效应器。在这两个实验系统中，都实现了肿瘤排斥以及持久和长期的 TH 细胞抗肿瘤记忆，这负责保护动物免受随后的肿瘤细胞挑战。基于这些和其他研究人员的结果，我们提出 AAA 是触发适应性免疫功能的关键因素，导致从促进肿瘤的微环境转向抗肿瘤的微环境、肿瘤排斥和获得抗肿瘤免疫记忆。讨论了涉及这些方法的神经免疫网络的假设。这些考虑对于理解化疗和/或放射疗法如何有助于阻断和/或根除肿瘤以及构建合适的抗肿瘤疫苗策略也很重要。
