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.

中文翻译：

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头颈癌中口腔与侧翼淋巴结 T 细胞反应增强与抗 PD1 疗效相似

了解头颈组织特异性免疫反应对于阐明头颈鳞状细胞癌 (HNSCC) 的免疫治疗耐药机制非常重要。在本研究中，我们旨在研究临床前模型中口腔和皮下胁腹肿瘤移植之间的 HNSCC 特异性免疫反应差异。将 MOC1 同基因小鼠口腔癌细胞系或表达来自卵清蛋白 (MOC1OVA) 或 ZsGreen (MOC1ZsGreen) 的 H2Kb 限制性 SIINFEKL 肽的版本接种到小鼠口腔粘膜（颊间隙）或皮下胁腹中，并比较肿瘤中的免疫细胞动力学和肿瘤引流淋巴结 (TDLN) 和抗 PD1 反应。与皮下侧翼肿瘤相比，原位口服 MOC1OVA 在原发肿瘤和 TDLN 中诱导了更多数量的 OVA 特异性 T 细胞、PD1 + 或 CD69 + 激活的 OVA 特异性 T 细胞。侧腹部位的肿瘤也较大，CD8 去除消除了两个部位之间肿瘤重量的差异。口服与侧腹 SIINFEKL 肽疫苗接种相比，前者的 TDLN 淋巴细胞反应增强。值得注意的是，来自口服 TDLN 的 cDC1 显示出增强的抗原摄取和共刺激标记物表达，从而引发抗原特异性 T 细胞反应增加和活化 T 细胞增加。口腔部位的亲本 MOC1 显示 TDLN 中内源性抗原反应性 T 细胞增加，抗 PD1 阻断可抑制口腔 MOC1 肿瘤，但不能抑制皮下侧翼 MOC1。总的来说，我们发现原位口腔模型和异位皮下模型之间存在明显的免疫反应，包括 TDLN 中 cDC1 的启动，揭示了头颈癌临床前研究的重要意义。