Increased PD-1(+) and TIM-3(+) TILs during Cetuximab Therapy Inversely Correlate with Response in Head and Neck Cancer Patients.
Increased PD-1(+) and TIM-3(+) TILs during Cetuximab Therapy Inversely Correlate with Response in Head and Neck Cancer Patients.
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DOI：
10.1158/2326-6066.cir-16-0333
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发表时间：
2017-05
影响因子：
10.1
通讯作者：
Ferris RL
中科院分区：
文献类型：
--
作者：
Jie HB;Srivastava RM;Argiris A;Bauman JE;Kane LP;Ferris RL
尽管免疫检查点受体在调节T细胞效应子功能中的重要作用逐渐得到认可，但尚不清楚其表达是否参与决定西妥昔单抗治疗的临床结果。我们检测了西妥昔单抗治疗期间头颈癌（HNSCC）患者CD 8+肿瘤浸润淋巴细胞（TIL）的免疫检查点受体（包括PD-1、CTLA-4和TIM-3）和溶细胞分子（包括颗粒酶B和穿孔素）的表达模式，并将其与外周血T淋巴细胞（PBL）的表达模式进行了比较。与CD 8 + PBL相比，CD 8 + TIL中PD-1和TIM-3表达的频率显著增加（分别为P = 0.008和P = 0.02）。这种增加的CD 8 + TIL群体共表达颗粒酶B/穿孔素和PD-1/TIM-3，这表明这些免疫检查点受体在CD 8 + TIL的西妥昔单抗促进细胞溶解活性中的调节作用。事实上，PD-1+和TIM-3+ CD 8 + TIL的频率增加与西妥昔单抗治疗的临床结局呈负相关。这些发现支持使用PD-1和TIM-3作为生物标志物，以反映西妥昔单抗治疗期间肿瘤微环境中CD 8 + T细胞的免疫状态。阻断这些免疫检查点受体可能会增强基于西妥昔单抗的癌症免疫治疗，以逆转CD 8 + TIL功能障碍，从而可能改善HNSCC患者的临床结局。
Despite emerging appreciation for the important role of immune checkpoint receptors in regulating the effector functions of T cells, it is unknown whether their expression is involved in determining the clinical outcome in response to cetuximab therapy. We examined the expression patterns of immune checkpoint receptors (including PD-1, CTLA-4, and TIM-3) and cytolytic molecules (including granzyme B and perforin) of CD8+ tumor-infiltrating lymphocytes (TILs) and compared them to those of peripheral blood T lymphocytes (PBLs) in patients with head and neck cancer (HNSCC) during cetuximab therapy. The frequency of PD-1 and TIM-3 expression was significantly increased in CD8+ TILs compared to CD8+ PBLs (P = 0.008 and P = 0.02, respectively). This increased CD8+ TIL population co-expressed granzyme B/perforin and PD-1/TIM-3, which suggests a regulatory role for these immune checkpoint receptors in cetuximab-promoting cytolytic activities of CD8+ TIL. Indeed, the increased frequency of PD-1+ and TIM-3+ CD8+ TILs was inversely correlated with clinical outcome of cetuximab therapy. These findings support the use of PD-1 and TIM-3 as biomarkers to reflect immune status of CD8+ T cells in the tumor microenvironment during cetuximab therapy. Blockade of these immune checkpoint receptors might enhance cetuximab-based cancer immunotherapy to reverse CD8+ TIL dysfunction, thus potentially improving clinical outcomes of HNSCC patients.