Tumor Vaccine Group, Center for Translational Medicine in Women's Health, University of Washington, 850 Republican Street, Seattle, WA 98109, USA.
Breast Cancer Res Treat. 2013 Jun;139(3):657-65. doi: 10.1007/s10549-013-2577-z. Epub 2013 Jun 8.
Numerous lines of evidence demonstrate that breast cancer is immunogenic; yet, there are few biologically relevant immune targets under investigation restricting the exploration of vaccines to limited breast cancer subtypes. Insulin-like growth factor-I receptor (IGF-IR) is a promising vaccine candidate since it is overexpressed in most breast cancer subtypes, is part of a dominant cancer growth pathway, and has been validated as a therapeutic target. We questioned whether IGF-IR was immunogenic in cancer patients. IGF-IR-specific IgG antibodies were significantly elevated in early-stage breast cancer patients at the time of diagnosis as compared to volunteer donors (p = 0.04). Predicted T-helper epitopes, derived from the IGF-IR extracellular and transmembrane domains, elicited a significantly higher incidence of Th2 immunity in breast cancer patients as compared to controls (p = 0.01). Moreover, the magnitude of Th2 immunity was greater in breast cancer patients compared to controls (p = 0.02). In contrast, both breast cancer patients and volunteer donors demonstrated a similar incidence of Th1 immunity to IGF-IR domains with the predominant response directed against epitopes in the intracellular domain of the protein. As the incidence of IGF-IR type I immunity was not associated with a breast cancer diagnosis, we questioned whether other factors were contributing to the presence of IGF-IR-specific T-cells in both populations. While age was not associated with Th1 immunity, we observed a significantly greater magnitude of IGF-IR IFN-γ-secreting T-cells in obese subjects as compared to overweight (p < 0.001) or healthy-weight (p = 0.006) subjects, regardless of breast cancer diagnosis. No significant difference was observed for Th2 incidence or magnitude when stratified by age (p = 0.174, p = 0.966, respectively) or body mass index (p = 0.137, p = 0.174, respectively). Our data demonstrate that IGF-IR is a tumor antigen and IGF-IR-specific Th1 immunity may be associated with obesity rather than malignancy.
大量证据表明乳腺癌具有免疫原性；然而，由于可供研究的具有生物学相关性的免疫靶点有限，这限制了疫苗在有限的乳腺癌亚型中的探索。胰岛素样生长因子-I 受体 (IGF-IR) 是一种很有前途的疫苗候选物，因为它在大多数乳腺癌亚型中过度表达，是主导癌症生长途径的一部分，并已被验证为治疗靶点。我们质疑 IGF-IR 在癌症患者中是否具有免疫原性。与志愿者供体相比，在诊断时早期乳腺癌患者的 IGF-IR 特异性 IgG 抗体显著升高（p = 0.04）。源自 IGF-IR 细胞外和跨膜结构域的预测辅助性 T 细胞表位在乳腺癌患者中引起 Th2 免疫的发生率明显高于对照组（p = 0.01）。此外，与对照组相比，乳腺癌患者的 Th2 免疫程度更大（p = 0.02）。相比之下，乳腺癌患者和志愿者供体对 IGF-IR 结构域的 Th1 免疫均具有相似的发生率，主要反应针对该蛋白细胞内结构域的表位。由于 IGF-IR Ⅰ型免疫的发生率与乳腺癌诊断无关，我们质疑其他因素是否导致这两种人群中都存在 IGF-IR 特异性 T 细胞。虽然年龄与 Th1 免疫无关，但我们观察到肥胖患者 IGF-IR IFN-γ 分泌 T 细胞的数量明显多于超重（p < 0.001）或健康体重（p = 0.006）患者，无论是否患有乳腺癌。当按年龄分层（p = 0.174，p = 0.966）或体重指数分层（p = 0.137，p = 0.174）时，未观察到 Th2 发生率或程度的显著差异。我们的数据表明 IGF-IR 是一种肿瘤抗原，IGF-IR 特异性 Th1 免疫可能与肥胖有关，而与恶性肿瘤无关。
