Interleukin-10 Is a Promising Marker for Immune-Related Adverse Events in Patients With Non-Small Cell Lung Cancer Receiving Immunotherapy

Overview

Journal Front Immunol

Specialty Allergy & Immunology

Date 2022 Feb 28

PMID 35222434

Authors

Haowei Wang

Fei Zhou

Chao Zhao

Lei Cheng

Caicun Zhou

Meng Qiao

Xuefei Li

Xiaoxia Chen

Affiliations

Soon will be listed here.

Abstract

Background: Immune checkpoint inhibitors (ICIs) brought about a major paradigm shift in non-small cell lung cancer (NSCLC) treatment. However, the use of ICIs is related to an unforeseeable pattern of immune-related adverse events (irAEs). Hence, more precise biomarkers are needed to predict the incidence of irAEs to prevent overtreatment of ICIs and decrease occurrences of irAEs. This study was designed to identify capable clinical features and plasma inflammatory factors for predicting irAEs.

Methods: A total of 67 patients who received ICI monotherapy or ICI-based combination therapy were retrospectively identified. Clinical characteristics and plasma inflammatory cytokines were collected and analyzed to screen potential biological markers associated with irAEs. The chi-square test, Fisher's test, and the Mann-Whitney U test were performed for the primary analysis. The optimal cutoff value was determined by a receiver operating characteristic (ROC) curve. Univariate and multivariate logistic regression models were used to identify risk factors of irAEs. Univariate and multivariate Cox proportional hazards were also performed.

Results: Out of 67 patients, 40 (59.7%) experienced irAEs, and 7 (10.4%) experienced severe adverse events (grade ≥ 3). Among these analyzed immune profile biomarkers, only interleukin-10 (IL-10) was related to the risk of irAEs. A high baseline IL-10 plasma level (odds ratio (OR) = 5.318, 95% CI 1.174-24.081, p = 0.030) was found to be a tremendous and independent risk factor for the development of irAEs. Also, for the dynamic analysis, upregulation of IL-10 after one cycle of ICI treatment was positively related to the occurrence of irAEs (OR = 5.712, 95% CI 1.088-29.993, p = 0.039). When pneumonitis, the most common irAEs, was analyzed, only baseline high-expression IL-10 was accompanied with the incidence of pneumonitis (OR = 9.969, 95% CI 1.144-86.843, p = 0.037).

Conclusion: Baseline and dynamic IL-10 plasma levels are tremendously and independently related to higher risk in the development of irAEs and could be utilized for medical practice to monitor adverse events in patients with ICI treatment.

Citing Articles

Personalization of Cancer Treatment: Exploring the Role of Chronotherapy in Immune Checkpoint Inhibitor Efficacy.

Fey R, Billo A, Clister T, Doan K, Berry E, Tibbitts D Cancers (Basel). 2025; 17(5).

PMID: 40075580 PMC: 11899640. DOI: 10.3390/cancers17050732.

Grade ≥ 3 hematologic adverse events of immunotherapy in advanced NSCLC patients: a systematic review and meta-analysis.

Wang S, Cai M, Xiong Y, Guo T, Niu X, Chen Y Eur J Clin Pharmacol. 2025; .

PMID: 39841181 DOI: 10.1007/s00228-025-03803-z.

Prognostic role of serum cytokines level in non-small cell lung cancer patients with anti-PD-1 and chemotherapy combined treatment.

Liu H, Zhou C, Jiang H, Chu T, Zhong R, Zhang X Front Immunol. 2024; 15:1430301.

PMID: 39502692 PMC: 11534701. DOI: 10.3389/fimmu.2024.1430301.

Kao C, Charmsaz S, Alden S, Brancati M, Li H, Balaji A J Clin Invest. 2024; 134(20).

PMID: 39403935 PMC: 11473156. DOI: 10.1172/JCI176567.

IL-22: A key inflammatory mediator as a biomarker and potential therapeutic target for lung cancer.

Xu L, Cao P, Wang J, Zhang P, Hu S, Cheng C Heliyon. 2024; 10(17):e35901.

PMID: 39263114 PMC: 11387261. DOI: 10.1016/j.heliyon.2024.e35901.

References

Tarhini A, Zahoor H, Lin Y, Malhotra U, Sander C, Butterfield L . Baseline circulating IL-17 predicts toxicity while TGF-β1 and IL-10 are prognostic of relapse in ipilimumab neoadjuvant therapy of melanoma. J Immunother Cancer. 2015; 3:39. PMC: 4570556. DOI: 10.1186/s40425-015-0081-1. View

Hulsmans M, Sager H, Roh J, Valero-Munoz M, Houstis N, Iwamoto Y . Cardiac macrophages promote diastolic dysfunction. J Exp Med. 2018; 215(2):423-440. PMC: 5789416. DOI: 10.1084/jem.20171274. View

Weber J, DAngelo S, Minor D, Hodi F, Gutzmer R, Neyns B . Nivolumab versus chemotherapy in patients with advanced melanoma who progressed after anti-CTLA-4 treatment (CheckMate 037): a randomised, controlled, open-label, phase 3 trial. Lancet Oncol. 2015; 16(4):375-84. DOI: 10.1016/S1470-2045(15)70076-8. View

Garon E, Rizvi N, Hui R, Leighl N, Balmanoukian A, Eder J . Pembrolizumab for the treatment of non-small-cell lung cancer. N Engl J Med. 2015; 372(21):2018-28. DOI: 10.1056/NEJMoa1501824. View

Li R, Qu H, Wang S, Wei J, Zhang L, Ma R . GDCRNATools: an R/Bioconductor package for integrative analysis of lncRNA, miRNA and mRNA data in GDC. Bioinformatics. 2018; 34(14):2515-2517. DOI: 10.1093/bioinformatics/bty124. View

Itakura E, Huang R, Wen D, Paul E, Wunsch P, Cochran A . IL-10 expression by primary tumor cells correlates with melanoma progression from radial to vertical growth phase and development of metastatic competence. Mod Pathol. 2011; 24(6):801-9. PMC: 3106125. DOI: 10.1038/modpathol.2011.5. View

Barbie D, Tamayo P, Boehm J, Kim S, Moody S, Dunn I . Systematic RNA interference reveals that oncogenic KRAS-driven cancers require TBK1. Nature. 2009; 462(7269):108-12. PMC: 2783335. DOI: 10.1038/nature08460. View

Jarry A, Bossard C, Bou-Hanna C, Masson D, Espaze E, Denis M . Mucosal IL-10 and TGF-beta play crucial roles in preventing LPS-driven, IFN-gamma-mediated epithelial damage in human colon explants. J Clin Invest. 2008; 118(3):1132-42. PMC: 2230656. DOI: 10.1172/JCI32140. View

McDermott D, Haanen J, Chen T, Lorigan P, ODay S . Efficacy and safety of ipilimumab in metastatic melanoma patients surviving more than 2 years following treatment in a phase III trial (MDX010-20). Ann Oncol. 2013; 24(10):2694-2698. DOI: 10.1093/annonc/mdt291. View

10.

Harbour S, Maynard C, Zindl C, Schoeb T, Weaver C . Th17 cells give rise to Th1 cells that are required for the pathogenesis of colitis. Proc Natl Acad Sci U S A. 2015; 112(22):7061-6. PMC: 4460486. DOI: 10.1073/pnas.1415675112. View

11.

Robert C, Schachter J, Long G, Arance A, Grob J, Mortier L . Pembrolizumab versus Ipilimumab in Advanced Melanoma. N Engl J Med. 2015; 372(26):2521-32. DOI: 10.1056/NEJMoa1503093. View

12.

Nakamura Y . Biomarkers for Immune Checkpoint Inhibitor-Mediated Tumor Response and Adverse Events. Front Med (Lausanne). 2019; 6:119. PMC: 6549005. DOI: 10.3389/fmed.2019.00119. View

13.

Haratani K, Hayashi H, Chiba Y, Kudo K, Yonesaka K, Kato R . Association of Immune-Related Adverse Events With Nivolumab Efficacy in Non-Small-Cell Lung Cancer. JAMA Oncol. 2017; 4(3):374-378. PMC: 6583041. DOI: 10.1001/jamaoncol.2017.2925. View

14.

Pestka S, Krause C, Sarkar D, Walter M, Shi Y, Fisher P . Interleukin-10 and related cytokines and receptors. Annu Rev Immunol. 2004; 22:929-79. DOI: 10.1146/annurev.immunol.22.012703.104622. View

15.

Robert C, Ribas A, Wolchok J, Hodi F, Hamid O, Kefford R . Anti-programmed-death-receptor-1 treatment with pembrolizumab in ipilimumab-refractory advanced melanoma: a randomised dose-comparison cohort of a phase 1 trial. Lancet. 2014; 384(9948):1109-17. DOI: 10.1016/S0140-6736(14)60958-2. View

16.

Chen X, Zhang Z, Hou X, Zhang Y, Zhou T, Liu J . Immune-related pneumonitis associated with immune checkpoint inhibitors in lung cancer: a network meta-analysis. J Immunother Cancer. 2020; 8(2). PMC: 7462235. DOI: 10.1136/jitc-2020-001170. View

17.

Tanaka R, Okiyama N, Okune M, Ishitsuka Y, Watanabe R, Furuta J . Serum level of interleukin-6 is increased in nivolumab-associated psoriasiform dermatitis and tumor necrosis factor-α is a biomarker of nivolumab recativity. J Dermatol Sci. 2017; 86(1):71-73. DOI: 10.1016/j.jdermsci.2016.12.019. View

18.

Newman A, Liu C, Green M, Gentles A, Feng W, Xu Y . Robust enumeration of cell subsets from tissue expression profiles. Nat Methods. 2015; 12(5):453-7. PMC: 4739640. DOI: 10.1038/nmeth.3337. View

19.

Johnson D, Chandra S, Sosman J . Immune Checkpoint Inhibitor Toxicity in 2018. JAMA. 2018; 320(16):1702-1703. DOI: 10.1001/jama.2018.13995. View

20.

Valpione S, Pasquali S, Campana L, Piccin L, Mocellin S, Pigozzo J . Sex and interleukin-6 are prognostic factors for autoimmune toxicity following treatment with anti-CTLA4 blockade. J Transl Med. 2018; 16(1):94. PMC: 5896157. DOI: 10.1186/s12967-018-1467-x. View