PERK+ Macrophages Drive Immunotherapy Resistance in Lymph Node Metastases of Oral Squamous Cell Carcinoma.

However, the pathologic response of lymph node (LN) metastases remains poorly understood.

然而，淋巴结(LN)转移的病理反应仍然不为人知。

This study aims to systematically evaluate the pathologic response rates (pRR) of LN metastases in patients with OSCC and identify potential targets to improve therapeutic outcomes.

本研究旨在系统评估口腔鳞状细胞癌(OSCC)患者的淋巴结(LN)转移的病理反应率(pRR)，并识别潜在靶点以改善治疗结果。

patients_and_methods

We assessed the pRRs of LN metastases and matched primary tumors (PT) in patients with OSCC enrolled in a randomized, two-arm, phase II clinical trial (NCT04649476).

我们在一项随机、双臂、II期临床试验(NCT04649476)中评估了口腔鳞状细胞癌(OSCC)患者的淋巴结(LN)转移和匹配的原发肿瘤(PT)的病理反应率(pRR)。

Single-cell and spatial transcriptomics and multiplex IHC were performed to analyze the tumor microenvironment and identify potential therapeutic targets in LN metastases.

通过单细胞和空间转录组学以及多重免疫组化技术，分析了淋巴结转移瘤的肿瘤微环境，并识别了潜在的治疗靶点。

A neoadjuvant orthotopic OSCC mouse model was established to evaluate the therapeutic potential of these targets.

建立了原位诱导的口腔鳞状细胞癌（OSCC）小鼠模型，以评估这些靶点的治疗潜力。

Results

We observed significant heterogeneity in pathologic regression of LN metastases, with lower pRRs compared with PTs. pRRs in LN metastases were correlated with overall and disease-free survival in patients with OSCC.

我们在淋巴结转移的病理退缩中观察到显著的异质性，与原发肿瘤相比，淋巴结转移的病理反应率较低。淋巴结转移的病理反应率与口腔鳞状细胞癌患者的总生存和无病生存相关。

We identified an abundance of macrophages in LN metastases exhibiting an unfolded protein response and activated protein kinase RNA-like endoplasmic reticulum kinase (PERK) signaling.

我们发现淋巴结转移中存在大量表现出未折叠蛋白反应和激活的蛋白激酶RNA样内质网激酶（PERK）信号传导的巨噬细胞。

These macrophages contributed to an extracellular matrix-enriched microenvironment through interactions with fibroblasts, which hindered T cell-mediated cytotoxicity.

这些巨噬细胞通过与成纤维细胞的相互作用，促进了富含细胞外基质的微环境的形成，这阻碍了T细胞介导的细胞毒性。

Pharmacologic inhibition of the PERK pathway significantly enhanced anti-PD-1 therapy in LN metastases and PTs in the mouse model.

药理抑制PERK通路显著增强了小鼠模型中LN转移和原发肿瘤的抗PD-1治疗效果。

Conclusions

Our study confirms that the pathologic response of LN metastases in patients with OSCC undergoing neoadjuvant immunotherapy or immunochemotherapy is inferior to that of PTs.

我们的研究证实，接受新辅助免疫治疗或免疫化疗的口腔鳞状细胞癌（OSCC）患者的淋巴结（LN）转移病灶的病理反应低于原发肿瘤（PTs）的病理反应。

It suggests that targeting the PERK pathway in macrophages could be a potential strategy to enhance treatment outcomes.

这表明针对巨噬细胞中的PERK通路进行靶向可能是一种潜在的策略，以增强治疗效果。