NK Cell Infiltrates and HLA Class I Expression in Primary HER2+ Breast Cancer Predict and Uncouple Pathological Response and Disease-free Survival
NK Cell Infiltrates and HLA Class I Expression in Primary HER2+ Breast Cancer Predict and Uncouple Pathological Response and Disease-free Survival
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DOI：
10.1158/1078-0432.ccr-18-2365
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发表时间：
2019-03-01
影响因子：
11.5
通讯作者：
Albanell, Joan
中科院分区：
文献类型：
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作者：
Muntasell, Aura;Rojo, Federico;Albanell, Joan
目的：探讨肿瘤浸润性NK细胞(TI-NK细胞)和HLAI类肿瘤表达作为乳腺癌新辅助抗HER2抗体治疗反应的生物标志物的价值。实验设计：采用免疫组织化学方法检测两组HER2阳性乳腺癌患者[发现队列(n=42)和验证队列(n=71)]治疗前肿瘤活检组织中的TI-NK细胞和HLA-I的表达。根据国际标准对肿瘤浸润性淋巴细胞(TIL)进行评分。生物标志物与病理完全应答(PCR)和无病生存期(DFS)的相关性被调整为预后因素。结果：在发现队列和验证队列中，TI-NK细胞与聚合酶链式反应显著相关(P<；0.0001)，与临床病理因素无关。在发现和验证队列中，A-3TI-NK细胞/50倍高倍视野(HPF)截止值预测了PCR[OR，188(11-3154)；OR，19.5(5.3-71.8)]。在两组患者中，TI-NK细胞的存在与DFS延长相关[HR，0.07(0.01-0.6)；P=0.01；HR，0.3(0.08-1.3)；P=0.1]。在HER2阳性肿瘤中，NK细胞、活化的树突状细胞和CD8T细胞的基因表达特征呈正相关，支持NK细胞作为有效抗肿瘤免疫的替代细胞的价值。根据肿瘤HLA-I的表达对患者进行分层，以确定独立于pCR的低复发风险和高复发风险的患者。结论：本研究确定基线TI-NK细胞是一项独立的生物标志物，对于基于PCR的抗HER2抗体治疗具有很大的预测价值，并指出肿瘤HLA-I状态对于独立于PCR来确定患者预后的补充价值。
Purpose: We investigated the value of tumor-infiltrating NK (TI-NK) cells and HLA class I tumor expression as biomarkers of response to neoadjuvant anti-HER2 antibody-based treatment in breast cancer.Experimental Design: TI-NK cells and HLA-I were determined by IHC in pretreatment tumor biopsies from two cohorts of patients with HER2-positive breast cancer [discovery cohort (n = 42) and validation cohort (n = 71)]. Tumor-infiltrating lymphocytes (TIL) were scored according to international guidelines. Biomarker association with pathologic complete response (pCR) and disease-free survival (DFS) was adjusted for prognostic factors. Gene set variation analysis was used for determining immune cell populations concomitant to NK-cell enrichment in HER2-positive tumors from the Cancer Genome Atlas (n = 190).Results: TI-NK cells were significantly associated with pCR in the discovery cohort as well as in the validation cohort (P < 0.0001), independently of clinicopathologic factors. A-3 TI-NK cells/ 50x high-power field (HPF) cutoff predicted pCR in the discovery and validation cohort [OR, 188 (11-3154); OR, 19.5 (5.3-71.8)]. Presence of TI-NK cells associated with prolonged DFS in both patient cohorts [HR, 0.07 (0.01-0.6); P = 0.01; HR, 0.3 (0.08-1.3); P = 0.1]. NK-, activated dendritic-and CD8 T-cell gene expression signatures positively correlated in HER2-positive tumors, supporting the value of NK cells as surrogates of effective antitumor immunity. Stratification of patients by tumor HLA-I expression identified patients with low and high relapse risk independently of pCR.Conclusions: This study identifies baseline TI-NK cells as an independent biomarker with great predictive value for pCR to anti-HER2 antibody-based treatment and points to the complementary value of tumor HLA-I status for defining patient prognosis independently of pCR.