Department of Medical Oncology, Shanghai Pulmonary Hospital, Tongji University Medical School Cancer Institute, School of Medicine, Tongji University, Shanghai 200092, China.
Tongji University, No 1239 Siping Road, Shanghai 200433, China.
J Immunother Cancer. 2021 Aug;9(8). doi: 10.1136/jitc-2021-002554.
Immunotherapy has revolutionized therapeutic patterns of small cell lung cancer (SCLC). Human leukocyte antigen class II (HLA class II) is related to antitumor immunity. However, the implications of HLA class II in SCLC remain incompletely understood.
We investigated the expression patterns of HLA class II on tumor cells and tumor-infiltrating lymphocytes (TILs) by immunohistochemistry staining and its association with clinical parameters, immune markers, and recurrence-free survival (RFS) in 102 patients with stage I-III SCLC with radical surgery. Additionally, an HLA class II-based immune risk model was established by least absolute shrinkage and selection operator regression. With bioinformatics methods, we investigated HLA class II-related enrichment pathways and immune infiltration landscape in SCLC.
HLA class II on tumor cells and TILs was positively expressed in 9 (8.8%) and 45 (44.1%) patients with SCLC, respectively. HLA class II on TILs was negatively associated with lymph node metastasis and positively correlated with programmed death-ligand 1 (PD-L1) on TILs (p<0.001) and multiple immune markers (CD3, CD4, CD8, FOXP3; p<0.001). Lymph node metastasis (OR 0.314, 95% CI 0.118 to 0.838, p=0.021) and PD-L1 on TILs (OR 3.233, 95% CI 1.051 to 9.95, p=0.041) were independent predictive factors of HLA class II on TILs. HLA class II positivity on TILs prompted a longer RFS (40.2 months, 95% CI 31.7 to 48.7 vs 28.8 months, 95% CI 21.4 to 36.3, p=0.014). HLA class II on TILs, PD-L1 on TILs, CD4, and FOXP3 were enrolled in the immune risk model, which categorized patients into high-risk and low-risk groups and had better power for predicting the recurrence than tumor stage. Pathway enrichment analyses showed that patients with high HLA class II expression demonstrated signatures of transmembrane transportation, channel activity, and neuroactive ligand-receptor interaction. High-risk SCLC patients had a higher proportion of T follicular helper cells (p=0.034) and a lower proportion of activated memory CD4-positive T cells (p=0.040) and resting dendritic cells (p=0.045) versus low-risk patients.
HLA class II plays a crucial role in tumor immune microenvironment and recurrence prediction. This work demonstrates the prognostic and clinical values of HLA class II in patients with SCLC.
免疫疗法彻底改变了小细胞肺癌（SCLC）的治疗模式。人类白细胞抗原 II 类（HLA class II）与抗肿瘤免疫有关。然而，HLA class II 在 SCLC 中的意义仍不完全清楚。
我们通过免疫组织化学染色研究了 102 例接受根治性手术的 I-III 期 SCLC 患者肿瘤细胞和肿瘤浸润淋巴细胞（TILs）中 HLA class II 的表达模式及其与临床参数、免疫标志物和无复发生存（RFS）的关系。此外，还通过最小绝对收缩和选择算子回归建立了基于 HLA class II 的免疫风险模型。通过生物信息学方法，我们研究了 SCLC 中 HLA class II 相关的富集途径和免疫浸润景观。
在 102 例 SCLC 患者中，肿瘤细胞和 TILs 中 HLA class II 的阳性表达率分别为 8.8%和 44.1%。TILs 中的 HLA class II 与淋巴结转移呈负相关，与 TILs 上的程序性死亡配体 1（PD-L1）（p<0.001）和多种免疫标志物（CD3、CD4、CD8、FOXP3；p<0.001）呈正相关。淋巴结转移（OR 0.314，95%CI 0.118 至 0.838，p=0.021）和 TILs 上的 PD-L1（OR 3.233，95%CI 1.051 至 9.95，p=0.041）是 TILs 中 HLA class II 的独立预测因素。TILs 中 HLA class II 阳性提示 RFS 更长（40.2 个月，95%CI 31.7 至 48.7 vs 28.8 个月，95%CI 21.4 至 36.3，p=0.014）。TILs 中的 HLA class II、TILs 上的 PD-L1、CD4 和 FOXP3 被纳入免疫风险模型，该模型将患者分为高风险和低风险组，并且比肿瘤分期更能准确预测复发。通路富集分析表明，HLA class II 高表达的患者表现出跨膜转运、通道活性和神经活性配体-受体相互作用的特征。与低危患者相比，高危 SCLC 患者滤泡辅助 T 细胞（p=0.034）比例更高，激活的记忆性 CD4+T 细胞（p=0.040）和静息树突状细胞（p=0.045）比例更低。
HLA class II 在肿瘤免疫微环境和复发预测中发挥着关键作用。本研究证明了 HLA class II 在 SCLC 患者中的预后和临床价值。
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