Department of Medical Oncology, Dana-Farber Cancer Institute and Harvard Medical School, Boston, MA 02115, USA.
Cancer Immunol Immunother. 2012 May;61(5):655-65. doi: 10.1007/s00262-011-1124-1. Epub 2011 Oct 28.
Therapeutic targeting of melanoma antigens frequently focuses on the melanocyte differentiation or cancer-testis families. Antigen-loss variants can often result, as these antigens are not critical for tumor cell survival. Exploration of functionally relevant targets has been limited. The melanoma inhibitor of apoptosis protein (ML-IAP; livin) is overexpressed in melanoma, contributing to disease progression and treatment resistance. Improved understanding of the significance of ML-IAP immune responses in patients has possible therapeutic applications. We found ML-IAP frequently expressed in melanoma metastases by immunohistochemistry. To assess spontaneous immunity to ML-IAP, an overlapping peptide library representing full-length protein was utilized to screen cellular responses in stage I-IV patients and healthy controls by ELISPOT. A broad array of CD4(+) and CD8(+) cellular responses against ML-IAP was observed with novel class I and class II epitopes identified. Specific HLA-A*0201 epitopes were analyzed further for frequency of reactivity. The generation of specific CD4(+) and cytotoxic T cells revealed potent functional capability including cytokine responsiveness to melanoma cell lines and tumor cell killing. In addition, recombinant ML-IAP protein used in an ELISA demonstrated high titer antibody responses in a subset of patients. Several melanoma patients who received CTLA-4 blockade with ipilimumab developed augmented humoral immune responses to ML-IAP as a function of treatment which was associated with beneficial clinical outcomes. High frequency immune responses in melanoma patients, associations with favorable treatment outcomes, and its essential role in melanoma pathogenesis support the development of ML-IAP as a disease marker and therapeutic target.
治疗性靶向黑色素瘤抗原通常集中在黑素细胞分化或癌症-睾丸家族。由于这些抗原对肿瘤细胞的存活不是至关重要的，因此通常会出现抗原缺失变体。对功能相关靶点的探索受到限制。黑色素瘤凋亡抑制蛋白（ML-IAP；livin）在黑色素瘤中过度表达，导致疾病进展和治疗耐药。对 ML-IAP 免疫反应在患者中的意义的深入了解可能具有治疗应用。我们通过免疫组织化学发现 ML-IAP 在黑色素瘤转移中经常表达。为了评估对 ML-IAP 的自发免疫，利用代表全长蛋白的重叠肽文库通过 ELISPOT 筛选 I-IV 期患者和健康对照的细胞反应。观察到针对 ML-IAP 的广泛的 CD4(+)和 CD8(+)细胞反应，鉴定出新型的 I 类和 II 类表位。进一步分析了特异性 HLA-A*0201 表位的反应频率。特异性 CD4(+)和细胞毒性 T 细胞的产生揭示了强大的功能能力，包括对黑色素瘤细胞系的细胞因子反应性和肿瘤细胞杀伤。此外，在 ELISA 中使用重组 ML-IAP 蛋白显示出在亚组患者中具有高滴度的抗体反应。一些接受 ipilimumab 治疗 CTLA-4 阻断的黑色素瘤患者由于治疗而对 ML-IAP 产生增强的体液免疫反应，这与有益的临床结果相关。黑色素瘤患者中高频率的免疫反应、与有利的治疗结果的关联以及其在黑色素瘤发病机制中的重要作用支持将 ML-IAP 作为疾病标志物和治疗靶点的开发。
