Weber Manuel, Ries Jutta, Braun Kristina, Wehrhan Falk, Distel Luitpold, Geppert Carol, Lutz Rainer, Kesting Marco, Trumet Leah
Department of Oral and Cranio-Maxillofacial Surgery, Uniklinikum Erlangen, Friedrich-Alexander-Universität Erlangen-Nürnberg (FAU), Glückstraße 11, 91054 Erlangen, Germany.
Deutsches Zentrum Immuntherapie (DZI), Comprehensive Cancer Center Erlangen-EMN (CCC ER-EMN), Friedrich-Alexander-Universität Erlangen-Nürnberg (FAU), 91054 Erlangen, Germany.
Cells. 2024 Feb 25;13(5):397. doi: 10.3390/cells13050397.
The first-line treatment of oral squamous cell carcinoma (OSCC) involves surgical tumor resection, followed by adjuvant radio(chemo)therapy (R(C)T) in advanced cases. Neoadjuvant radio- and/or chemotherapy has failed to show improved survival in OSCC. Recently, neoadjuvant immunotherapy has shown promising therapeutic efficacy in phase 2 trials. In this context, the addition of radio- and chemotherapy is being reconsidered. Therefore, a better understanding of the tumor-biologic effects of neoadjuvant RCT would be beneficial. The current study was conducted on a retrospective cohort of patients who received neoadjuvant RCT for the treatment of oral cancer. The aim of the study was to evaluate the influence of neoadjuvant RCT on the immunological tumor microenvironment (TME) and hypoxic and glucose metabolisms.
A cohort of 45 OSSC tissue samples from patients were analyzed before and after RCT (total 50.4 Gy; 1.8 Gy 5× weekly; Cisplatin + 5-Fluorouracil). Immunohistochemistry for CD68, CD163, TGF-β, GLUT-1 and HIF-1α was performed using tissue microarrays and automated cell counting. Differences in expression before and after RCT and associations with histomorphological parameters (T-status, N-status) were assessed using the Mann-Whitney U test.
Tumor resection specimens after neoadjuvant RCT showed a significant decrease in CD68 infiltration and a significant increase in CD163 cell density. The CD68/CD163 ratio was significantly lower after RCT, indicating a shift toward M2 polarization. The GLUT-1 and HIF-1α expressions were significantly lower after RCT. Larger tumors (T3/T4) showed a lower GLUT-1 expression. Other biomarkers were not associated with the T- and N-status.
Neoadjuvant RCT with 50.4 Gy induced a shift toward the M2 polarization of macrophages in the TME. This change in immune composition is not favorable and may be prognostically negative and counteract immunotherapeutic approaches. In addition, the decreased expressions in GLUT-1 and HIF-1α indicate reductions in the glucose metabolism and hypoxic energy metabolism in response to "high dose" neoadjuvant RCT, which may be therapeutically desirable.
口腔鳞状细胞癌（OSCC）的一线治疗包括手术切除肿瘤，晚期病例随后进行辅助放（化）疗（R（C）T）。新辅助放化疗未能显示出可提高OSCC患者的生存率。最近，新辅助免疫疗法在2期试验中显示出有前景的治疗效果。在这种背景下，放化疗的联合应用正在被重新考虑。因此，更好地了解新辅助RCT的肿瘤生物学效应将是有益的。本研究对接受新辅助RCT治疗口腔癌的患者进行回顾性队列研究。该研究的目的是评估新辅助RCT对免疫肿瘤微环境（TME）以及缺氧和葡萄糖代谢的影响。
对45例患者的OSCC组织样本在RCT前后（总量50.4 Gy；每周5次，每次1.8 Gy；顺铂 + 5-氟尿嘧啶）进行分析。使用组织芯片和自动细胞计数法对CD68、CD163、转化生长因子-β（TGF-β）、葡萄糖转运蛋白1（GLUT-1）和缺氧诱导因子-1α（HIF-1α）进行免疫组织化学检测。使用曼-惠特尼U检验评估RCT前后表达的差异以及与组织形态学参数（T分期、N分期）的相关性。
新辅助RCT后的肿瘤切除标本显示CD68浸润显著减少，CD163细胞密度显著增加。RCT后CD68/CD163比值显著降低，表明向M2极化转变。RCT后GLUT-1和HIF-1α表达显著降低。较大的肿瘤（T3/T4）显示GLUT-1表达较低。其他生物标志物与T分期和N分期无关。
50.4 Gy的新辅助RCT诱导TME中的巨噬细胞向M2极化转变。这种免疫组成的变化是不利的，可能在预后方面是负面的，并可能抵消免疫治疗方法。此外，GLUT-1和HIF-1α表达的降低表明，响应“高剂量”新辅助RCT，葡萄糖代谢和缺氧能量代谢减少，这在治疗上可能是可取的。
