Department of Laboratory Medicine and Pathobiology, University of Toronto, Toronto, Ontario, Canada. Laboratory Medicine Program, University Health Network, Toronto, Ontario, Canada.
Lunenfeld-Tanenbaum Research Institute, Mount Sinai Hospital, Toronto, Ontario, Canada.
Cancer Immunol Res. 2016 Jan;4(1):41-8. doi: 10.1158/2326-6066.CIR-15-0051. Epub 2015 Nov 6.
We previously observed T-bet(+) lymphocytes to be associated with a good prognosis in a cohort of women with familial breast cancer. To validate this finding, we evaluated lymphocyte T-bet expression in an independent unselected prospectively accrued series of women with lymph node-negative breast carcinoma. T-bet and clinicopathologic data were available for 614 women. Hormone receptors, HER2, Ki-67, CK5, EGFR, p53, and T-bet status were determined using IHC and/or biochemical methods. Tumors were assigned to luminal A, luminal B, HER2, and basal subtypes based on the expression of IHC markers. Multiple cutpoints were examined in a univariate penalized Cox model to stratify tumors into T-bet(+/high) and T-bet(-/low). Fisher exact test was used to analyze T-bet associations with clinicopathologic variables, IHC markers, and molecular subtype. Survival analyses were by the Cox proportional hazards model. All tests were two sided. A test with a P value < 0.05 was considered statistically significant. T-bet(+/high) tumor status was significantly associated with large tumor size, high grade, hormone receptor negativity, CK5, EGFR and p53 positivity, high Ki-67, and basal subtype. With a median follow-up of 96.5 months, T-bet(-/low) tumor status was associated with a reduced disease-free survival compared with T-bet(+/high) tumor status in multivariate analysis (P = 0.0027; relative risk = 5.62; 95% confidence intervals, 1.48-50.19). Despite being associated with adverse clinicopathologic characteristics, T-bet(+) tumor-infiltrating lymphoid cells are associated with a favorable outcome. This supports their role in Th1-mediated antitumor activity and may provide insight for the development of new therapeutic strategies.
我们之前观察到 T-bet(+)淋巴细胞与家族性乳腺癌女性患者的良好预后相关。为了验证这一发现，我们评估了 T-bet 表达在一组独立的、未经选择的、前瞻性募集的淋巴结阴性乳腺癌女性患者中的表达情况。有 614 名女性的 T-bet 和临床病理数据可用。使用免疫组化和/或生化方法确定激素受体、HER2、Ki-67、CK5、EGFR、p53 和 T-bet 状态。根据免疫组化标志物的表达，将肿瘤分为 luminal A、luminal B、HER2 和基底亚型。在单变量惩罚 Cox 模型中检查了多个切点，以将肿瘤分层为 T-bet(+/高)和 T-bet(-/低)。Fisher 确切检验用于分析 T-bet 与临床病理变量、免疫组化标志物和分子亚型的相关性。生存分析采用 Cox 比例风险模型。所有检验均为双侧。P 值<0.05 被认为具有统计学意义。T-bet(+/高)肿瘤状态与肿瘤较大、分级较高、激素受体阴性、CK5、EGFR 和 p53 阳性、Ki-67 较高和基底亚型显著相关。在中位随访 96.5 个月后，多变量分析显示 T-bet(-/低)肿瘤状态与疾病无进展生存相关（P=0.0027；相对风险=5.62；95%置信区间，1.48-50.19）。尽管 T-bet(+)肿瘤浸润性淋巴细胞与不良的临床病理特征相关，但与 T-bet(+/高)肿瘤状态相关，提示其在 Th1 介导的抗肿瘤活性中的作用，并可能为新的治疗策略的发展提供思路。
