Department of Pathology, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China.
Front Immunol. 2022 Jul 22;13:942154. doi: 10.3389/fimmu.2022.942154. eCollection 2022.
Immune checkpoint modulation has been a vital therapeutic option in many malignancies, and targeting of novel immune checkpoints, including OX40/OX40L costimulatory signaling, is being assessed in clinical trials. However, little is known about the role of OX40 and OX40L in pancreatic ductal adenocarcinoma (PDAC). Thus, we investigated the clinical significance of OX-40 and OX40L and their associations with alternative immune checkpoints, immune infiltrates, clinicopathological features, and clinical outcomes. We performed multiplexed immunofluorescence staining for OX40, OX40L, CD8, and CD68 using tissue microarrays from 255 patients. Immunohistochemistry data for PD-L1, B7-H3, B7-H4, CD3, and Foxp3 were analyzed. And the RNA sequencing data of OX40/OX40L in The Cancer Genome Atlas and International Cancer Genome Consortium databases were also evaluated. The positive rates for OX40 on tumor cells (TCs) and immune cells (ICs) were 8.6% and 10.2%, respectively, and the positive rates for OX40L on TCs, ICs, and macrophages were 20%, 40.4%, and 12.9%, respectively. OX40 was associated with favorable clinicopathological features. OX40+ on ICs, OX40L+ on TCs, or OX40L+ on macrophages, rather than the total gene and protein levels of OX40/OX40L, were associated with improved survival. OX40+ on ICs and OX40L+ on macrophages were independent factors of clinical outcomes. Moreover, we could more accurately stratify patients through the combination of OX40 on ICs and OX40L on TCs, and patients with OX40+ ICs and OX40L+CK+ showed the best outcome. And we demonstrated that patients with OX40-ICs and low CD8+ T cells infiltration had unfavorable survival. Intriguingly, OX40+ ICs or OX40L+ macrophages demonstrated superior survival in patients with PD-L1 negativity than in those with PD-L1 positivity. Furthermore, OX40+ ICs were correlated with negative B7-H4 on TCs, high densities of CD3 T cells, and high densities of Foxp3 T cells; OX40+ TCs and OX40L+ TCs were associated with low densities of Foxp3 T cells. We identified OX40 and OX40L as promising predictors for prognosis in PDAC.
免疫检查点调节已成为许多恶性肿瘤的重要治疗选择，针对包括 OX40/OX40L 共刺激信号在内的新型免疫检查点的靶向治疗正在临床试验中进行评估。然而，关于 OX40 和 OX40L 在胰腺导管腺癌（PDAC）中的作用知之甚少。因此，我们研究了 OX-40 和 OX40L 的临床意义及其与其他免疫检查点、免疫浸润、临床病理特征和临床结果的关联。我们使用 255 名患者的组织微阵列进行了 OX40、OX40L、CD8 和 CD68 的多重免疫荧光染色。分析了 PD-L1、B7-H3、B7-H4、CD3 和 Foxp3 的免疫组化数据。还评估了癌症基因组图谱和国际癌症基因组联盟数据库中 OX40/OX40L 的 RNA 测序数据。肿瘤细胞（TCs）和免疫细胞（ICs）上 OX40 的阳性率分别为 8.6%和 10.2%，TCs、ICs 和巨噬细胞上 OX40L 的阳性率分别为 20%、40.4%和 12.9%。OX40 与有利的临床病理特征相关。IC 上的 OX40+、TC 上的 OX40L+或巨噬细胞上的 OX40L+，而不是 OX40/OX40L 的总基因和蛋白水平，与生存改善相关。IC 上的 OX40+和巨噬细胞上的 OX40L+是临床结局的独立因素。此外，我们可以通过结合 IC 上的 OX40 和 TCs 上的 OX40L 更准确地对患者进行分层，并且 OX40+ICs 和 OX40L+CK+的患者表现出最佳的结果。我们还证明，OX40-ICs 且 CD8+T 细胞浸润低的患者生存不佳。有趣的是，与 PD-L1 阳性患者相比，OX40+ICs 或 OX40L+巨噬细胞的患者具有更好的生存优势。此外，IC 上的 OX40+与 TCs 上的 B7-H4 阴性、CD3 T 细胞密度高和 Foxp3 T 细胞密度高相关；TC 上的 OX40+和 OX40L+与 Foxp3 T 细胞密度低有关。我们将 OX40 和 OX40L 确定为 PDAC 预后的有前途的预测因子。
