Purpose: To evaluate the tissue distribution and clinical significance of OX40 and OX40L in human non–small cell lung cancer (NSCLC). Experimental Design: Using multiplexed quantitative immunofluorescence, we conducted simultaneous and localized measurements of OX40 and OX40L proteins, major T-cell subsets, and conventional type 1 dendritic cells (cDC1) in 614 primary NSCLCs from three independent cohorts represented in tissue microarrays. We also measured OX40L protein in samples from a phase I clinical trial of intratumor administration of a lipid nanoparticle encapsulated mRNA encoding OX40L (mRNA-2416) in human solid tumors. Finally, we studied the OX40 pathway in 212 uterine/ovarian serous carcinomas. Results: OX40 protein was expressed in approximately 90% of NSCLCs, and OX40L was detected in approximately 10% of cases. Increased expression of OX40 was associated with higher CD4+ and CD8+ T lymphocytes, as well as cDC1s. Elevated expression of OX40L was consistently associated with increased CD4+ tumor-infiltrating lymphocytes and longer overall survival. No association was found between OX40 or OX40L levels and oncogenic driver mutations in EGFR and KRAS in lung adenocarcinomas. Delivering OX40L mRNA using intratumor mRNA-2416 injection mediated increased local OX40L protein levels that was most prominent in a patient with ovarian serous carcinoma. Detectable OX40L protein levels were observed in 15% of primary uterine/ovarian serous malignancies and associated with longer survival. Conclusions: The OX40 pathway is expressed in a fraction of NSCLCs and is associated with a favorable immune contexture. Although OX40L is uncommonly expressed in NSCLC and serous malignancies, it is associated with better prognosis and can be introduced using exogenous mRNA.

中文翻译：

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OX40/OX40L 通路在人类非小细胞肺癌中的空间定位和免疫调节作用

目的：评价OX40和OX40L在人非小细胞肺癌（NSCLC）中的组织分布和临床意义。实验设 我们还测量了来自人类实体瘤中编码 OX40L (mRNA-2416) 的脂质纳米颗粒封装 mRNA 的肿瘤内给药的 I 期临床试验样品中的 OX40L 蛋白。最后，我们研究了 212 例子宫/卵巢浆液性癌中的 OX40 通路。结果： OX40 蛋白在大约 90% 的 NSCLC 中表达，并且在大约 10% 的病例中检测到 OX40L。OX40 的表达增加与较高的 CD4+ 和 CD8+ T 淋巴细胞以及 cDC1s 相关。OX40L 表达升高始终与 CD4+ 肿瘤浸润淋巴细胞增加和总生存期延长相关。未发现 OX40 或 OX40L 水平与肺腺癌中 EGFR 和 KRAS 的致癌驱动突变之间存在关联。使用肿瘤内 mRNA-2416 注射递送 OX40L mRNA 可提高局部 OX40L 蛋白水平，这在卵巢浆液性癌患者中最为显着。在 15% 的原发性子宫/卵巢浆液性恶性肿瘤中观察到可检测的 OX40L 蛋白水平，并且与更长的生存期相关。结论：OX40 通路在部分 NSCLC 中表达，并与良好的免疫环境相关。