PO.IM01.08 · 免疫学
联合表观遗传治疗揭示非经典新抗原以改善卵巢癌的过继T细胞疗法
Combination epigenetic therapy unmasks non-canonical neoantigens to improve adoptive T cell therapy in ovarian cancer
作者与单位 Authors & Affiliations
摘要 Abstract
中文摘要
免疫治疗已彻底改变了一系列恶性肿瘤的癌症治疗，然而由于肿瘤突变负荷低和新抗原可用性有限，其在卵巢癌(OC)中的疗效仍然有限。虽然目前的免疫治疗策略难以取得持久应答，但将过继T细胞疗法(ATT)与扩展抗原格局的表观遗传疗法相结合，为克服OC中固有的免疫抵抗挑战提供了一条有前景的途径。表观遗传重塑既能增加肿瘤免疫原性，也能去抑制"隐匿抗原"——这些抗原通常在转录上沉默，却在恶性细胞中选择性表达。这些隐匿抗原源自错误剪接、可变开放阅读框和内源性逆转录元件，它们产生可被T细胞识别的HLA限制性肽。它们在癌细胞中的选择性表达和免疫原性突显了这些非经典靶点用于免疫治疗的可操作性。我们用DNA甲基转移酶和组蛋白去乙酰化酶抑制剂处理四种OC细胞系，并鉴定出一组可重复的上调的蛋白质编码隐匿抗原，包括内源性逆转录病毒(ERV)和其他内源性逆转录元件。随后我们生成了一个覆盖所鉴定靶点的重叠肽库，用于激发和扩增来自健康供者PBMC的T细胞。所得的T细胞产品在多个肽库中表现出强劲的增殖、抗原特异性细胞因子产生和高亲和力应答。功能亲和力测定证实了对表观遗传诱导的抗原靶点的特异性识别。这些结果表明，表观遗传治疗能够揭示OC中先前无法触及的肿瘤特异性抗原库，并能生成针对这些隐匿抗原的强效T细胞产品。因此，利用表观遗传诱导隐匿抗原表达可能提供一条扩展ATT靶点格局并改善卵巢癌治疗疗效的途径。
查看英文原文 English abstract
Immunotherapy has revolutionized cancer treatment across a range of malignancies, yet its efficacy in ovarian cancer (OC) has remained limited due to low tumor mutational burden and limited neoantigen availability. While current immunotherapy strategies have struggled to achieve durable responses, adoptive T cell therapy (ATT) combined with epigenetic therapies that expand the antigenic landscape present a promising avenue to overcome the inherent challenges of immune resistance in OC. Epigenetic remodeling can increase tumor immunogenicity as well as de-repress “cryptic antigens”, that are normally transcriptionally silent yet selectively expressed in malignant cells. These cryptic antigens arise from mis-splicing, alternative open reading frames, and endogenous retroelements that generate HLA-restricted peptides recognizable by T cells. Their selective expression in cancer cells and immunogenicity highlight the actionability of these non-canonical targets for immunotherapy. We treated four OC cell lines with DNA methyltransferase and histone deacetylase inhibitors and identified a reproducible subset of upregulated protein-coding cryptic antigens, including endogenous retroviruses (ERVs) and other endogenous retroelements. We then generated an overlapping peptide library spanning the identified targets to prime and expand T cells from PBMCs of healthy donors. The resultant T cell products demonstrated robust proliferation, antigen-specific cytokine production, and high-avidity responses across multiple peptide pools. Functional avidity assays confirmed specific recognition of epigenetically induced antigen targets. These results demonstrate that epigenetic therapy can uncover a previously inaccessible tumor-specific antigen pool in OC and enable the generation of potent T cell products directed against these cryptic antigens. Leveraging epigenetic induction of cryptic antigen expression may thus provide path a to expand the target landscape for ATT and improve therapeutic efficacy in ovarian cancer.
利益披露 Disclosure
J. A. Colina, None..
K. B. Chiappinelli, None..
E. E. Grundy, None.