Institute of Pathology, University Hospital Schleswig-Holstein, Campus Lübeck, Lübeck, Germany.
Department of Otorhinolaryngology, University Hospital Schleswig-Holstein, Campus Lübeck, Lübeck, Germany.
Clin Cancer Res. 2021 Jan 15;27(2):632-644. doi: 10.1158/1078-0432.CCR-20-0197. Epub 2020 Oct 27.
Recurrent tumors (RT) of head and neck squamous cell carcinoma (HNSCC) occur in up to 60%, with poor therapeutic response and detrimental prognosis. We hypothesized that HNSCC RTs successfully evade antitumor immune response and aimed to reveal tumor immune microenvironment (TIME) changes of primary tumors (PT) and corresponding RTs.
Tumor-infiltrating leukocytes (TIL) of 300 PTs and 108 RTs from two large independent and clinically well-characterized HNSCC cohorts [discovery cohort (DC), validation cohort (VD)] were compared by IHC. mRNA expression analysis of 730 immune-related genes was performed for 18 PTs and RTs after adjuvant chemoradiotherapy (CRT). The effect of chemotherapy and radiation resistance was assessed with an spheroid/immunocyte coculture model.
TIME analysis revealed overall decrease of TILs with significant loss of CD8 T cells (DC = 0.045/VC < 0.0001) and B lymphocytes (DC = 0.036/VC < 0.0001) in RTs compared with PTs in both cohorts. Decrease predominantly occurred in RTs after CRT. Gene expression analysis confirmed loss of TILs ( = 0.0004) and B lymphocytes ( < 0.0001) and showed relative increase of neutrophils ( = 0.018), macrophages ( < 0.0001), dendritic cells ( = 0.0002), and mast cells ( = 0.0057) as well as lower overall expression of immune-related genes ( = 0.018) in RTs after CRT. Genes involved in B-lymphocyte functions and number of tertiary lymphoid structures showed the strongest decrease. and were upregulated and , indicating their potential suitability as therapeutic targets in CRT resistance.
HNSCC RTs have an immunosuppressive TIME, which is particularly apparent after adjuvant CRT and might substantially contribute to poor therapeutic response and prognosis.
头颈部鳞状细胞癌（HNSCC）的复发性肿瘤（RT）发生率高达 60%，治疗反应差，预后不良。我们假设 HNSCC RT 成功逃避了抗肿瘤免疫反应，并旨在揭示原发性肿瘤（PT）和相应 RT 的肿瘤免疫微环境（TIME）变化。
通过免疫组化比较了两个大型独立且临床特征良好的 HNSCC 队列[发现队列（DC），验证队列（VD）]的 300 个 PT 和 108 个 RT 的肿瘤浸润白细胞（TIL）。对 18 个接受辅助放化疗（CRT）后的 PT 和 RT 进行了 730 个免疫相关基因的 mRNA 表达分析。使用球体/免疫细胞共培养模型评估了化疗和放疗耐药的影响。
TIME 分析显示，与 PT 相比，两组 RT 的 TIL 总体减少，CD8 T 细胞（DC = 0.045/VC < 0.0001）和 B 淋巴细胞（DC = 0.036/VC < 0.0001）显著减少。这种减少主要发生在 CRT 后的 RT 中。基因表达分析证实，TIL（ = 0.0004）和 B 淋巴细胞（ < 0.0001）减少，同时中性粒细胞（ = 0.018）、巨噬细胞（ < 0.0001）、树突状细胞（ = 0.0002）和肥大细胞（ = 0.0057）相对增加，以及 CRT 后 RT 中整体免疫相关基因表达降低（ = 0.018）。涉及 B 淋巴细胞功能和三级淋巴结构数量的基因减少最为明显。和上调，表明它们作为 CRT 耐药的潜在治疗靶点的潜在适用性。
HNSCC RT 具有免疫抑制性 TIME，特别是在辅助 CRT 后更为明显，这可能是治疗反应和预后不良的主要原因。
