Purpose: Neoadjuvant anti-PD1 (aPD1) therapies are being explored in surgically resectable head and neck squamous cell carcinoma (HNSCC). Encouraging responses have been observed but further insights into the mechanisms underlying resistance and approaches to improve responses are needed. Experimental Design: We integrated data from syngeneic mouse oral carcinoma (MOC) models and neoadjuvant pembrolizumab HNSCC patient tumor RNA-Seq data to explore the mechanism of aPD1 resistance. Tumors and tumor draining lymph nodes (DLN) from MOC models were analyzed for antigen specific priming. CCL5 expression was enforced in an aPD1 resistant model. Results: An aPD1 resistant mouse model showed poor priming in the tumor DLN due to type 1 conventional dendritic cell (cDC1) dysfunction, which correlated with exhausted and poorly responsive antigen specific T cells. Tumor microenvironment analysis also showed decreased cDC1 in aPD1 resistant tumors compared to sensitive tumors. Following neoadjuvant aPD1 therapy, pathologic responses in patients also positively correlated with baseline transcriptomic cDC1 signatures. In an aPD1 resistant model, intra-tumoral cDC1 vaccine was sufficient to restore aPD1 response by enhancing T cell infiltration and increasing antigen-specific responses with improved tumor control. Mechanistically, CCL5 expression significantly correlated with neoadjuvant aPD1 response and enforced expression of CCL5 in an aPD1 resistant model enhanced cDC1 tumor infiltration, restored antigen specific responses, and recovered sensitivity to aPD1 treatment. Conclusions: These data highlight the contribution of tumor infiltrating cDC1s in HNSCC aPD1 response, and approaches to enhance cDC1 infiltration and function that may circumvent aPD1 resistance in HNSCC patients.

中文翻译：

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针对树突状细胞功能障碍，规避头颈癌中的抗 PD1 耐药性

目的：正在探索新辅助抗 PD1 (aPD1) 疗法治疗可手术切除的头颈鳞状细胞癌 (HNSCC)。已经观察到了令人鼓舞的反应，但需要进一步了解耐药性的机制和改善反应的方法。实验设计：我们整合了同基因小鼠口腔癌 (MOC) 模型的数据和新辅助派姆单抗 HNSCC 患者肿瘤 RNA-Seq 数据，以探索 aPD1 耐药机制。对来自 MOC 模型的肿瘤和肿瘤引流淋巴结 (DLN) 进行抗原特异性引发分析。CCL5 表达在 aPD1 抗性模型中得到加强。结果：aPD1 抗性小鼠模型由于 1 型常规树突状细胞 (cDC1) 功能障碍而显示肿瘤 DLN 启动不良，这与抗原特异性 T 细胞耗尽且反应不佳相关。肿瘤微环境分析还显示，与敏感肿瘤相比，aPD1 耐药肿瘤中的 cDC1 减少。新辅助 aPD1 治疗后，患者的病理反应也与基线转录组 cDC1 特征呈正相关。在aPD1耐药模型中，肿瘤内cDC1疫苗足以通过增强T细胞浸润和增加抗原特异性反应以及改善肿瘤控制来恢复aPD1反应。从机制上讲，CCL5 表达与新辅助 aPD1 反应显着相关，并且在 aPD1 耐药模型中 CCL5 的强制表达增强了 cDC1 肿瘤浸润，恢复了抗原特异性反应，并恢复了对 aPD1 治疗的敏感性。结论：这些数据强调了肿瘤浸润的 cDC1 在 HNSCC aPD1 反应中的贡献，以及增强 cDC1 浸润和功能的方法，可能会规避 HNSCC 患者的 aPD1 耐药性。