Soluble Immune Checkpoint-Related Proteins in Blood Are Associated With Invasion and Progression in Non-Small Cell Lung Cancer

Qinchuan Wang; Yue He; Wanlu Li; Xiaohang Xu; Qingfeng Hu; Zilong Bian; Andi Xu; Huakang Tu; Ming Wu; Xifeng Wu

doi:10.3389/fimmu.2022.887916

Soluble Immune Checkpoint-Related Proteins in Blood Are Associated With Invasion and Progression in Non-Small Cell Lung Cancer

Front Immunol. 2022 Jul 6:13:887916. doi: 10.3389/fimmu.2022.887916. eCollection 2022.

Authors

Qinchuan Wang^{1

2

3}, Yue He^{1

3}, Wanlu Li^{1

3}, Xiaohang Xu^{1

3}, Qingfeng Hu^{1

3}, Zilong Bian^{1

3}, Andi Xu^{1

3}, Huakang Tu^{1

3}, Ming Wu⁴, Xifeng Wu^{1

3}

Affiliations

¹ Center for Biostatistics, Bioinformatics and Big Data, The Second Affiliated Hospital and School of Public Health, Zhejiang University School of Medicine, Hangzhou, China.
² Department of Surgical Oncology, Affiliated Sir Run Run Shaw Hospital, Zhejiang University School of Medicine, Hangzhou, China.
³ The Key Laboratory of Intelligent Preventive Medicine of Zhejiang Province, Hangzhou, China.
⁴ Department of Thoracic Surgery, Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China.

Abstract

Background: Immune checkpoint inhibition therapy has been achieved significant success in the treatment of non-small cell lung cancer (NSCLC). However, the role of soluble immune checkpoint- related proteins in NSCLC remains obscure.

Methods: We evaluated the circulating levels of 14 immune checkpoint-related proteins panel (BTLA, LAG-3, GITR, IDO, PD-L2, PD-L1, PD-1, HVEM, Tim-3, CD28, CD27, CD80, CD137 and CTLA-4) and their associations with the risk of invasive disease and the risk of NSCLC in 43 pre-invasive (AIS), 81 invasive NSCLC (IAC) patients and matched 35 healthy donors using a multiplex Luminex assay. Gene expression in tumors from TCGA were analyzed to elucidate potential mechanisms. The multivariate logistic regression model was applied in the study. ROC(receiver operator characteristic) curve and calibration curve were used in the performance evaluation.

Results: We found that sCD27, sCD80, CD137 and sPDL2 levels were significantly increased in IAC cases compared to AIS cases (P= 1.05E-06, 4.44E-05, 2.30E-05 and 1.16E-06, respectively), whereas sPDL1 and sPDL2 levels were significantly increased in NSCLC cases compared to healthy controls (P=3.25E-05 and 1.49E-05, respectively). Unconditional univariate logistic regression analysis indicated that increased sCD27, sCD80, sCD137, and sPDL2 were significantly correlated with the risk of invasive diseases. The model with clinical variables, sCD27 and sPDL2 demonstrated the best performance (AUC=0.845) in predicting the risk of IAC. CD27 and PDCD1LG2 (PDL2) showed significant association with cancer invasion signature in TCGA dataset.

Conclusion: Our study provides evidence that soluble immune checkpoint-related proteins may associate with the risk of IAC, and we further established an optimized multivariate predictive model, which highlights their potential application in the treatment of NSCLC patients. Future studies may apply these biomarkers to test their predictive value of survival and treatment outcome during immunotherapy in NSCLC patients.

Keywords: adenocarcinoma in situ; invasive adenocarcinoma; non-small cell lung cancer; prediction model; soluble immune checkpoint-related protein.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Carcinoma, Non-Small-Cell Lung* / pathology
Humans
Immune Checkpoint Proteins / genetics
Immunotherapy
Lung Neoplasms* / pathology

Substances

Immune Checkpoint Proteins