Heninger Erika, Krueger Timothy E G, Thiede Stephanie M, Sperger Jamie M, Byers Brianna L, Kircher Madison R, Kosoff David, Yang Bing, Jarrard David F, McNeel Douglas G, Lang Joshua M
Department of Medicine, University of Wisconsin, Madison, Madison, WI 53705, USA.
University of Wisconsin Carbone Cancer Center, Madison, Madison, WI 53705, USA.
Oncotarget. 2016 Dec 20;7(51):84359-84374. doi: 10.18632/oncotarget.12711.
Immune tolerance to self-antigens can limit robust anti-tumor immune responses in the use of tumor vaccines. Expression of novel tumor associated antigens can improve immune recognition and lysis of tumor cells. The cancer-testis antigen (CTA) family of proteins has been hypothesized to be an ideal class of antigens due to tumor-restricted expression, a subset of which have been found to induce antibody responses in patients with prostate disease. We demonstrate that CTA expression is highly inducible in five different Prostate Cancer (PC) cell lines using a hypomethylating agent 5-Aza-2'-deoxycytidine (5AZA) and/or a histone deacetylase inhibitor LBH589. These CTAs include NY-ESO1, multiple members of the MAGE and SSX families and NY-SAR35. A subset of CTAs is synergistically induced by the combination of 5AZA and LBH589. We developed an ex vivo organ culture using human PC biopsies for ex vivo drug treatments to evaluate these agents in clinical samples. These assays found significant induction of SSX2 in 9/9 distinct patient samples and NY-SAR35 in 7/9 samples. Further, we identify expression of SSX2 in circulating tumor cells (CTC) from patients with advanced PC. These results indicate that epigenetic modifying agents can induce expression of a broad range of neoantigens in human PC and may serve as a useful adjunctive therapy with novel tumor vaccines and checkpoint inhibitors.
对自身抗原的免疫耐受可能会限制肿瘤疫苗应用中强大的抗肿瘤免疫反应。新型肿瘤相关抗原的表达可改善对肿瘤细胞的免疫识别和裂解。癌症-睾丸抗原（CTA）蛋白家族由于在肿瘤中受限表达，被认为是一类理想的抗原，其中一部分已被发现可在前列腺疾病患者中诱导抗体反应。我们证明，使用去甲基化剂5-氮杂-2'-脱氧胞苷（5AZA）和/或组蛋白去乙酰化酶抑制剂LBH589，CTA在五种不同的前列腺癌（PC）细胞系中具有高度诱导性。这些CTA包括NY-ESO1、MAGE和SSX家族的多个成员以及NY-SAR35。5AZA和LBH589联合使用可协同诱导一部分CTA。我们开发了一种利用人PC活检组织进行体外药物处理的体外器官培养方法，以在临床样本中评估这些药物。这些检测发现，在9/9个不同的患者样本中SSX2有显著诱导，在7/9个样本中NY-SAR35有显著诱导。此外，我们在晚期PC患者的循环肿瘤细胞（CTC）中鉴定出了SSX2的表达。这些结果表明，表观遗传修饰剂可诱导人PC中多种新抗原的表达，并可能作为新型肿瘤疫苗和检查点抑制剂的有用辅助疗法。
