T-helper I immunity, specific for the breast cancer antigen insulin-like growth factor-I receptor (IGF-IR), is associated with increased adiposity
T-helper I immunity, specific for the breast cancer antigen insulin-like growth factor-I receptor (IGF-IR), is associated with increased adiposity
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DOI：
10.1007/s10549-013-2577-z
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发表时间：
2013-06-01
影响因子：
3.8
通讯作者：
Disis, Mary L.
中科院分区：
文献类型：
--
作者：
Cecil, Denise L.;Park, Kyong Hwa;Disis, Mary L.
大量证据表明，乳腺癌是免疫原性的；然而，很少有生物学上相关的免疫靶点正在研究中，限制了对有限乳腺癌亚型的疫苗探索。胰岛素样生长因子- 1受体（IGF-IR）是一种很有希望的候选疫苗，因为它在大多数乳腺癌亚型中过表达，是主要癌症生长途径的一部分，并已被证实是一种治疗靶点。我们质疑IGF-IR在癌症患者中是否具有免疫原性。早期乳腺癌患者诊断时的igf - ir特异性IgG抗体明显高于志愿供体（p = 0.04）。与对照组相比，来自IGF-IR细胞外和跨膜结构域的预测t辅助表位在乳腺癌患者中引起了显著更高的Th2免疫发生率（p = 0.01）。此外，与对照组相比，乳腺癌患者的Th2免疫水平更高（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免疫发生率相似，主要反应是针对IGF-IR蛋白的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，我们质疑是否有其他因素导致了这两种人群中IGF-IR特异性t细胞的存在。虽然年龄与Th1免疫无关，但我们观察到，与超重（p < 0.001）或健康体重（p = 0.006）的受试者相比，肥胖受试者的IGF-IR ifn - γ分泌t细胞显著增加，而与乳腺癌诊断无关。按年龄（p = 0.174, p = 0.966）或体重指数（p = 0.137, p = 0.174）分层时，Th2的发病率或程度无显著差异。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，而不是与恶性肿瘤有关。
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-gamma-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.