Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA, United States; Department of Otolaryngology - Head and Neck Surgery, Asahikawa Medical University, Asahikawa, Japan.
Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA, United States.
Oral Oncol. 2024 May;152:106795. doi: 10.1016/j.oraloncology.2024.106795. Epub 2024 Apr 9.
Understanding head and neck tissue specific immune responses is important for elucidating immunotherapy resistance mechanisms to head and neck squamous cell carcinoma (HNSCC). In this study, we aimed to investigate HNSCC-specific immune response differences between oral and subcutaneous flank tumor transplantation in preclinical models.
The MOC1 syngeneic mouse oral carcinoma cell line or versions expressing either the H2Kb-restricted SIINFEKL peptide from ovalbumin (MOC1OVA) or ZsGreen (MOC1ZsGreen) were inoculated into mouse oral mucosa (buccal space) or subcutaneous flank and compared for immune cell kinetics in tumors and tumor-draining lymph nodes (TDLNs) and for anti-PD1 response.
Compared to subcutaneous flank tumors, orthotopic oral MOC1OVA induced a higher number of OVA-specific T cells, PD1 + or CD69 + activated OVA-specific T cells in both primary tumors and TDLNs. Tumors were also larger in the flank site and CD8 depletion eliminated the difference in tumor weight between the two sites. Oral versus flank SIINFEKL peptide vaccination showed enhanced TDLN lymphocyte response in the former site. Notably, cDC1 from oral TDLN showed enhanced antigen uptake and co-stimulatory marker expression, resulting in elicitation of an increased antigen specific T cell response and increased activated T cells. Parental MOC1 in the oral site showed increased endogenous antigen-reactive T cells in TDLNs and anti-PD1 blockade rejected oral MOC1 tumors but not subcutaneous flank MOC1.
Collectively, we find distinct immune responses between orthotopic oral and heterotopic subcutaneous models, including priming by cDC1 in TDLN, revealing important implications for head and neck cancer preclinical studies.
了解头颈部组织特异性免疫反应对头颈部鳞状细胞癌（HNSCC）免疫治疗耐药机制的研究具有重要意义。本研究旨在探讨临床前模型中口腔与皮下颊部肿瘤移植中 HNSCC 特异性免疫反应的差异。
采用 MOC1 同源小鼠口腔癌细胞系或表达卵清蛋白 SIINFEKL 肽（MOC1OVA）或 ZsGreen（MOC1ZsGreen）的 MOC1 细胞系，分别接种于小鼠口腔黏膜（颊腔）或皮下颊部，比较肿瘤和肿瘤引流淋巴结（TDLN）中免疫细胞动力学以及抗 PD1 反应。
与皮下颊部肿瘤相比，口腔 MOC1OVA 诱导更多的 OVA 特异性 T 细胞、原发性肿瘤和 TDLN 中 PD1+或 CD69+激活的 OVA 特异性 T 细胞。颊部肿瘤较大，CD8 耗竭消除了两个部位肿瘤重量的差异。口腔与颊部 SIINFEKL 肽疫苗接种显示前者 TDLN 淋巴细胞反应增强。值得注意的是，口腔 TDLN 的 cDC1 表现出增强的抗原摄取和共刺激标志物表达，从而引发更强的抗原特异性 T 细胞反应和更多的激活 T 细胞。口腔部位的亲本 MOC1 表现出 TDLN 中内源性抗原反应性 T 细胞增加，抗 PD1 阻断可排斥口腔 MOC1 肿瘤，但不能排斥皮下颊部 MOC1。
综上所述，我们发现原位口腔与异位皮下模型之间存在明显的免疫反应差异，包括 TDLN 中 cDC1 的启动，这对头颈部癌症临床前研究具有重要意义。
