Prospective longitudinal study of immune checkpoint molecule (ICM) expression in immune cell subsets during curative conventional therapy of head and neck squamous cell carcinoma (HNSCC)
Prospective longitudinal study of immune checkpoint molecule (ICM) expression in immune cell subsets during curative conventional therapy of head and neck squamous cell carcinoma (HNSCC)
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DOI：
10.1002/ijc.33446
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发表时间：
2020-12
影响因子：
6.4
通讯作者：
A. von Witzleben;A. Fehn;A. Grages;J. Ezić;S. Jeske;L. Puntigam;C. Brunner;J. Kraus;H. Kestler;J. Doescher;M. Brand;M. Theodoraki;C. Ottensmeier;T. Hoffmann;P. Schuler;S. Laban
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文献类型：
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作者：
A. von Witzleben;A. Fehn;A. Grages;J. Ezić;S. Jeske;L. Puntigam;C. Brunner;J. Kraus;H. Kestler;J. Doescher;M. Brand;M. Theodoraki;C. Ottensmeier;T. Hoffmann;P. Schuler;S. Laban
程序性死亡-1（PD 1）抗体获批用于复发性和转移性头颈部鳞状细胞癌。已经发现了多种靶向共刺激和共抑制免疫检查点分子（ICM）的药物。然而，在治疗过程中，这些ICM如何受到治疗性常规治疗对不同免疫细胞亚群的影响仍然是未知的。在题为“对治愈性常规治疗的免疫应答评价”的前瞻性非干预性临床研究（NCT 03053661）中，前瞻性入组了22例患者。在整个治愈性常规治疗和随访期间的规定时间点采集血样。通过流式细胞术评估来自不同时间点的免疫细胞（IC）。通过流式细胞术测量以下ICM：PD 1、CTLA 4、BTLA、CD 137、CD 27、GITR、OX 40、LAG 3和TIM 3。ICM表达的动力学采用非参数配对样本检验进行评估。在放疗期间或之后，观察到多种IC类型上的PD 1、BTLA和CD 27的显著变化。在CD 4 T细胞和CD 4 + CD 39 + T细胞中观察到OX 40和GITR表达从基线至RT结束增加的非显著趋势。在具有疾病复发样品的患者中，TIM 3和LAG 3阳性CD 4 + CD 39 + T细胞的非显著增加是明显的，伴随着TIM 3/LAG 3双阳性细胞的增加。在常规治疗和抗PD 1/PD-L中与RT联合的潜在未来靶点可能是BTLA激动剂或共刺激ICM（如CD 137、OX 40或GITR）的激动性抗体。西妥昔单抗与增强ADCC或靶向TIM 3/LAG 3的CD 27激动性抗体的组合可能是另一种有前景的策略。
Programmed‐death‐1 (PD1) antibodies are approved for recurrent and metastatic head and neck squamous cell carcinoma. Multiple drugs targeting costimulatory and coinhibitory immune checkpoint molecules (ICM) have been discovered. However, it remains unknown how these ICM are affected by curative conventional therapy on different immune cell subsets during the course of treatment. In the prospective noninterventional clinical study titled “Immune Response Evaluation to Curative conventional Therapy” (NCT03053661), 22 patients were prospectively enrolled. Blood samples were drawn at defined time points throughout curative conventional treatment and follow‐up. Immune cells (IC) from the different time points were assessed by multicolor flow cytometry. The following ICM were measured by flow cytometry: PD1, CTLA4, BTLA, CD137, CD27, GITR, OX40, LAG3 and TIM3. Dynamics of ICM expression were assessed using nonparametric paired samples tests. Significant changes were noted for PD1, BTLA and CD27 on multiple IC types during or after radiotherapy. Nonsignificant trends for increased expression of OX40 and GITR from baseline until the end of RT were observed on CD4 T cells and CD4+ CD39+ T cells. In patients with samples at recurrence of disease, a nonsignificant increase of TIM3 and LAG3 positive CD4+ CD39+ T cells was evident, accompanied by an increase of double positive cells for TIM3/LAG3. Potential future targets to be combined with RT in the conventional treatment and anti‐PD1/PD‐L could be BTLA agonists, or agonistic antibodies to costimulatory ICM like CD137, OX40 or GITR. The combination of cetuximab with CD27 agonistic antibodies enhancing ADCC or the targeting of TIM3/LAG3 may be another promising strategy.