Dzinic Sijana H, Bernardo Maria M, Oliveira Daniel S M, Wahba Marian, Sakr Wael, Sheng Shijie
1Department of Pathology, Wayne State University School of Medicine, Detroit, Michigan.
Bosn J Basic Med Sci. 2015 Oct 25;15(4):1-6. doi: 10.17305/bjbms.2015.783.
Despite the promising clinical outcome, the primary challenge of the curative cancer immunotherapy is to overcome the dichotomy of the immune response: tumor-evoked immunostimulatory versus tumor-induced immunosuppressive. The goal needs to be two-fold, to re-establish sustainable antitumor-cancer immunity and to eliminate immunosuppression. The successful elimination of cancer cells by immunosurveillance requires the antigenic presentation of the tumor cells or tumor-associated antigens and the expression of immunostimulatory cytokines and chemokines by cancer and immune cells. Tumors are heterogeneous and as such, some of the tumor cells are thought to have stem cell characteristics that enable them to suppress or desensitize the host immunity due to acquired epigenetic changes. A central mechanism underlying tumor epigenetic instability is the increased histone deacetylase (HDAC)-mediated repression of HDAC-target genes regulating homeostasis and differentiation. It was noted that pharmacological HDAC inhibitors are not effective in eliminating tumor cells partly because they may induce immunosuppression. We have shown that epithelial-specific tumor suppressor maspin, an ovalbumin-like non-inhibitory serine protease inhibitor, reprograms tumor cells toward better differentiated phenotypes by inhibiting HDAC1. Recently, we uncovered a novel function of maspin in directing host immunity towards tumor elimination. In this review, we discuss the maspin and maspin/HDAC1 interplay in tumor biology and immunology. We propose that maspin based therapies may eradicate cancer.
尽管癌症免疫疗法取得了令人鼓舞的临床效果，但其主要挑战在于克服免疫反应的二分法：肿瘤引发的免疫刺激与肿瘤诱导的免疫抑制。目标需要是双重的，即重新建立可持续的抗肿瘤免疫并消除免疫抑制。通过免疫监视成功消除癌细胞需要肿瘤细胞或肿瘤相关抗原的抗原呈递以及癌症和免疫细胞表达免疫刺激细胞因子和趋化因子。肿瘤是异质性的，因此，一些肿瘤细胞被认为具有干细胞特征，由于获得性表观遗传变化，这些特征使它们能够抑制或使宿主免疫脱敏。肿瘤表观遗传不稳定性的一个核心机制是组蛋白脱乙酰酶（HDAC）介导的对调节稳态和分化的HDAC靶基因的抑制增加。值得注意的是，药理学HDAC抑制剂在消除肿瘤细胞方面并不有效，部分原因是它们可能诱导免疫抑制。我们已经表明，上皮特异性肿瘤抑制因子maspin，一种卵清蛋白样非抑制性丝氨酸蛋白酶抑制剂，通过抑制HDAC1使肿瘤细胞重编程为更好的分化表型。最近，我们发现了maspin在引导宿主免疫消除肿瘤方面的新功能。在这篇综述中，我们讨论了maspin以及maspin/HDAC1在肿瘤生物学和免疫学中的相互作用。我们提出基于maspin的疗法可能根除癌症。
