Milne Katy, Barnes Rebecca O, Girardin Adam, Mawer Melanie A, Nesslinger Nancy J, Ng Alvin, Nielsen Julie S, Sahota Robert, Tran Eric, Webb John R, Wong May Q, Wick Darin A, Wray Andrew, McMurtrie Elissa, Köbel Martin, Kalloger Steven E, Gilks C Blake, Watson Peter H, Nelson Brad H
Trev and Joyce Deeley Research Centre, BC Cancer Agency, Victoria, British Columbia, Canada.
PLoS One. 2008;3(10):e3409. doi: 10.1371/journal.pone.0003409. Epub 2008 Oct 15.
Tumor-infiltrating CD8+ T cells are correlated with prolonged progression-free and overall survival in epithelial ovarian cancer (EOC). A significant fraction of EOC patients mount autoantibody responses to various tumor antigens, however the relationship between autoantibodies and tumor-infiltrating T cells has not been investigated in EOC or any other human cancer. We hypothesized that autoantibody and T cell responses may be correlated in EOC and directed toward the same antigens.
We obtained matched serum and tumor tissue from 35 patients with high-grade serous ovarian cancer. Serum samples were assessed by ELISA for autoantibodies to the common tumor antigen NY-ESO-1. Tumor tissue was examined by immunohistochemistry for expression of NY-ESO-1, various T cell markers (CD3, CD4, CD8, CD25, FoxP3, TIA-1 and Granzyme B) and other immunological markers (CD20, MHC class I and MHC class II). Lymphocytic infiltrates varied widely among tumors and included cells positive for CD3, CD8, TIA-1, CD25, FoxP3 and CD4. Twenty-six percent (9/35) of patients demonstrated serum IgG autoantibodies to NY-ESO-1, which were positively correlated with expression of NY-ESO-1 antigen by tumor cells (r = 0.57, p = 0.0004). Autoantibodies to NY-ESO-1 were associated with increased tumor-infiltrating CD8+, CD4+ and FoxP3+ cells. In an individual HLA-A2+ patient with autoantibodies to NY-ESO-1, CD8+ T cells isolated from solid tumor and ascites were reactive to NY-ESO-1 by IFN-gamma ELISPOT and MHC class I pentamer staining.
We demonstrate that tumor-specific autoantibodies and tumor-infiltrating T cells are correlated in human cancer and can be directed against the same target antigen. This implies that autoantibodies may collaborate with tumor-infiltrating T cells to influence clinical outcomes in EOC. Furthermore, serological screening methods may prove useful for identifying clinically relevant T cell antigens for immunotherapy.
肿瘤浸润性CD8 + T细胞与上皮性卵巢癌（EOC）患者无进展生存期和总生存期的延长相关。相当一部分EOC患者会对多种肿瘤抗原产生自身抗体反应，然而，在EOC或任何其他人类癌症中，自身抗体与肿瘤浸润性T细胞之间的关系尚未得到研究。我们推测，在EOC中自身抗体和T细胞反应可能相关，且针对相同抗原。
我们从35例高级别浆液性卵巢癌患者中获取了匹配的血清和肿瘤组织。通过ELISA检测血清样本中针对常见肿瘤抗原NY-ESO-1的自身抗体。通过免疫组织化学检查肿瘤组织中NY-ESO-1、各种T细胞标志物（CD3、CD4、CD8、CD25、FoxP3、TIA-1和颗粒酶B）以及其他免疫标志物（CD20、MHC I类和MHC II类）的表达情况。肿瘤之间的淋巴细胞浸润差异很大，包括CD3、CD8、TIA-1、CD25、FoxP3和CD4阳性的细胞。26%（9/35）的患者血清中存在针对NY-ESO-1的IgG自身抗体，这些抗体与肿瘤细胞中NY-ESO-1抗原的表达呈正相关（r = 0.57，p = 0 .0004）。针对NY-ESO-1的自身抗体与肿瘤浸润性CD8 +、CD4 +和FoxP3 +细胞的增加有关。在一名具有针对NY-ESO-1自身抗体的个体HLA-A2 +患者中，通过IFN-γ ELISPOT和MHC I类五聚体染色检测发现，从实体瘤和腹水中分离出的CD8 + T细胞对NY-ESO-1有反应。
我们证明，在人类癌症中肿瘤特异性自身抗体与肿瘤浸润性T细胞相关，且可针对相同的靶抗原。这意味着自身抗体可能与肿瘤浸润性T细胞协同作用，影响EOC的临床结局。此外，血清学筛查方法可能有助于识别用于免疫治疗的临床相关T细胞抗原。
