Philip Ramila, Murthy Sidhartha, Krakover Jonathan, Sinnathamby Gomathinayagam, Zerfass Jennifer, Keller Lorraine, Philip Mohan
Immunotope Inc., The Pennsylvania Biotechnology Center, 3805 Old Easton Road, Doylestown, Pennsylvania 18902, USA.
J Proteome Res. 2007 Jul;6(7):2509-17. doi: 10.1021/pr0606777. Epub 2007 Jun 5.
Elimination of cancer through early detection and treatment is the ultimate goal of cancer research and is especially critical for ovarian and other forms of cancer typically diagnosed at very late stages that have very poor response rates. Proteomics has opened new avenues for the discovery of diagnostic and therapeutic targets. Immunoproteomics, which defines the subset of proteins involved in the immune response, holds considerable promise for providing a better understanding of the early-stage immune response to cancer as well as important insights into antigens that may be suitable for immunotherapy. Early administration of immunotherapeutic vaccines can potentially have profound effects on prevention of metastasis and may potentially cure through efficient and complete tumor elimination. We developed a mass-spectrometry-based method to identify novel autoantibody-based serum biomarkers for the early diagnosis of ovarian cancer that uses native tumor-associated proteins immunoprecipitated by autoantibodies from sera obtained from cancer patients and from cancer-free controls to identify autoantibody signatures that occur at high frequency only in cancer patient sera. Interestingly, we identified a subset of more than 50 autoantigens that were also processed and presented by MHC class I molecules on the surfaces of ovarian cancer cells and thus were common to the two immunological processes of humoral and cell-mediated immunity. These shared autoantigens were highly representative of families of proteins with roles in key processes in carcinogenesis and metastasis, such as cell cycle regulation, cell proliferation, apoptosis, tumor suppression, and cell adhesion. Autoantibodies appearing at the early stages of cancer suggest that this detectable immune response to the developing tumor can be exploited as early-stage biomarkers for the development of ovarian cancer diagnostics. Correspondingly, because the T-cell immune response depends on MHC class I processing and presentation of peptides, proteins that go through this pathway are potential candidates for the development of immunotherapeutics designed to activate a T-cell immune response to cancer. To the best of our knowledge, this is the first comprehensive study that identifies and categorizes proteins that are involved in both humoral and cell-mediated immunity against ovarian cancer, and it may have broad implications for the discovery and selection of theranostic molecular targets for cancer therapeutics and diagnostics in general.
通过早期检测和治疗消除癌症是癌症研究的最终目标，对于卵巢癌和其他通常在非常晚期才被诊断出来且反应率极低的癌症形式而言尤为关键。蛋白质组学为发现诊断和治疗靶点开辟了新途径。免疫蛋白质组学定义了参与免疫反应的蛋白质子集，在更好地理解癌症早期免疫反应以及深入了解可能适用于免疫治疗的抗原方面具有巨大潜力。早期施用免疫治疗疫苗可能对预防转移产生深远影响，并有可能通过有效且彻底地消除肿瘤而治愈疾病。我们开发了一种基于质谱的方法，用于鉴定基于新型自身抗体的血清生物标志物，以早期诊断卵巢癌，该方法利用从癌症患者和无癌对照血清中通过自身抗体免疫沉淀的天然肿瘤相关蛋白来识别仅在癌症患者血清中高频出现的自身抗体特征。有趣的是，我们鉴定出了50多种自身抗原的子集，这些自身抗原也由卵巢癌细胞表面的MHC I类分子进行加工和呈递，因此是体液免疫和细胞介导免疫这两种免疫过程所共有的。这些共享的自身抗原高度代表了在致癌和转移的关键过程中发挥作用的蛋白质家族，如细胞周期调控、细胞增殖、细胞凋亡、肿瘤抑制和细胞黏附。癌症早期出现的自身抗体表明，这种对正在发展的肿瘤的可检测免疫反应可被用作卵巢癌诊断的早期生物标志物。相应地，由于T细胞免疫反应依赖于MHC I类对肽的加工和呈递，经过此途径的蛋白质是开发旨在激活针对癌症的T细胞免疫反应的免疫治疗药物的潜在候选物。据我们所知，这是第一项全面研究，鉴定并分类了参与针对卵巢癌的体液免疫和细胞介导免疫的蛋白质，它可能对癌症治疗和诊断的治疗诊断分子靶点的发现和选择具有广泛影响。
