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Cytokine profiling identifies circulating IL-6 and IL-15 as prognostic stratifiers in patients with non-small cell lung cancer receiving anti-PD-1/PD-L1 blockade therapy

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Abstract

Whether circulating levels of specific cytokines at baseline link with treatment efficacy of immune checkpoint blockade (ICB) therapy in patients with non-small cell lung cancer remains unknown. In this study, serum samples were collected in two independent, prospective, multicenter cohorts before the initiation of ICB. Twenty cytokines were quantified, and cutoff values were determined by receiver operating characteristic analyses to predict non-durable benefit. The associations of each dichotomized cytokine status with survival outcomes were assessed. In the discovery cohort (atezolizumab cohort; N = 81), there were significant differences in progression-free survival (PFS) in accordance with the levels of IL-6 (log-rank test, P = 0.0014), IL-15 (P = 0.00011), MCP-1 (P = 0.013), MIP-1β (P = 0.0035), and PDGF-AB/BB (P = 0.016). Of these, levels of IL-6 and IL-15 were also significantly prognostic in the validation cohort (nivolumab cohort, N = 139) for PFS (log-rank test, P = 0.011 for IL-6 and P = 0.00065 for IL-15) and overall survival (OS; P = 3.3E-6 for IL-6 and P = 0.0022 for IL-15). In the merged cohort, IL-6high and IL-15high were identified as independent unfavorable prognostic factors for PFS and OS. The combined IL-6 and IL-15 status stratified patient survival outcomes into three distinct groups for both PFS and OS. In conclusion, combined assessment of circulating IL-6 and IL-15 levels at baseline provides valuable information to stratify the clinical outcome of patients with non-small cell lung cancer treated with ICB. Further studies are required to decipher the mechanistic basis of this finding.

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Data availability

The datasets generated during and/or analyzed during the current study are available from the corresponding author on reasonable request.

Abbreviations

ALK:

Anaplastic lymphoma kinase

AUC:

Area under the curve

CI:

Confidence interval

DCB:

Durable clinical benefit

EGF:

Epidermal growth factor

EGFR:

Epidermal growth factor receptor

GM-CSF:

Granulocyte–macrophage colony-stimulating factor

HR:

Hazard ratio

ICB:

Immune checkpoint blockade

IFN:

Interferon

IL:

Interleukin

IL-1RA:

IL-1 receptor antagonist

IP-10:

IFN-γ-inducible protein 10

LIPI:

Lung immune prognostic index

MCP-1:

Monocyte chemoattractant protein-1

MIG:

Monokine induced by IFN-γ

MIP-1β:

Macrophage inflammatory protein-1β

NDB:

Non-durable benefit

OS:

Overall survival

PDGF:

Platelet-derived growth factor

PD-1:

Programmed cell death protein 1

PD-L1:

Programmed death-ligand 1

PFS:

Progression-free survival

PS:

Performance status

ROC:

Receiver operating characteristic

TNF:

Tumor necrosis factor

TPS:

Tumor proportion score

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Acknowledgements

The authors would like to thank the patients, their families, and all the investigators who participated in this study. We thank Gabrielle White Wolf, PhD, from Edanz (https://jp.edanz.com/ac) for editing a draft of this manuscript.

Funding

This work was supported by Chugai Pharmaceutical Co., Ltd. (Tokyo, Japan). The funder had no role in the study design, data collection and analysis, decision to publish, or preparation of the manuscript.

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Authors and Affiliations

  1. Second Division, Department of Internal Medicine, Hamamatsu University School of Medicine, 1-20-1 Handayama, Higashi-Ku, Hamamatsu, 431-3192, Japan

    Yusuke Inoue, Naoki Inui, Masato Karayama, Hideki Yasui, Hironao Hozumi, Yuzo Suzuki, Kazuki Furuhashi, Noriyuki Enomoto, Tomoyuki Fujisawa & Takafumi Suda

  2. Department of Clinical Pharmacology and Therapeutics, Hamamatsu University School of Medicine, 1-20-1 Handayama, Higashi-Ku, Hamamatsu, 431-3192, Japan

    Naoki Inui

  3. Department of Chemotherapy, Hamamatsu University School of Medicine, 1-20-1 Handayama, Higashi-Ku, Hamamatsu, 431-3192, Japan

    Masato Karayama

  4. Department of Respiratory Medicine, Shizuoka General Hospital, 4-27-1 Kita-Ando, Shizuoka, 420-8527, Japan

    Kazuhiro Asada

  5. Department of Respiratory Medicine, Shizuoka City Shizuoka Hospital, 10-93 Otemachi, Shizuoka, 420-8630, Japan

    Masato Fujii

  6. Department of Respiratory Medicine, Fujieda Municipal General Hospital, 4-1-11 Surugadai, Fujieda, 426-8677, Japan

    Shun Matsuura

  7. Department of Respiratory Medicine, Iwata City Hospital, 512-3 Ohkubo, Iwata, 438-8550, Japan

    Tomohiro Uto

  8. Department of Pulmonary Medicine, Seirei Hamamatsu General Hospital, 2-12-12 Sumiyoshi, Naka-Ku, Hamamatsu, 430-8558, Japan

    Dai Hashimoto

  9. Department of Respiratory Medicine, Seirei Mikatahara General Hospital, 3453 Mikatahara, Kita-Ku, Hamamatsu, 433-8558, Japan

    Takashi Matsui

  10. Department of Respiratory Medicine, Shizuoka Saiseikai General Hospital, 1-1-1 Oshika, Shizuoka, 422-8527, Japan

    Masaki Ikeda

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  1. Yusuke Inoue
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Contributions

YI was involved in conceptualization, acquisition of data, data curation, formal analysis, investigation, methodology, project administration, resources, supervision, validation, visualization, writing—original draft, and writing—review and editing. NI was involved in conceptualization, acquisition of data, data curation, funding acquisition, investigation, methodology, project administration, resources, supervision, validation, visualization, writing—original draft, and writing—review and editing. MK, KA, MF, SM, TU, DH, TM, MI, HY, HH, YS, KF, NE, TF and TS were responsible for acquisition of data, data curation, supervision, validation, writing—review and editing.

Corresponding author

Correspondence to Yusuke Inoue.

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Conflict of interest

The authors have no conflicts to declare.

Consent to participate

All patients provided written informed consent to participate in the study.

Ethical approval

This study was approved by the institutional review board at each site (Hamamatsu University School of Medicine, #18–164 for the discovery cohort and E16-051 for the validation cohort) and was conducted in accordance with the International Council for Harmonisation Good Clinical Practice guidelines and the Declaration of Helsinki. This study followed the Strengthening the Reporting of Observational Studies in Epidemiology (STROBE) reporting guidelines. This study was registered at the UMIN Clinical Trials Registry as UMIN000035616 and UMIN000022505.

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262_2023_3453_MOESM1_ESM.tif

Supplementary Figure S1. Receiver operating characteristic (ROC) curve analyses of serum IL-6 and IL-15 levels for the prediction of non-durable benefit. a ROC curve analysis of IL-6 levels in the discovery cohort. b ROC curve analysis of IL-15 levels in the discovery cohort. c ROC curve analysis of IL-6 levels in the validation cohort. d ROC curve analysis of IL-15 levels in the validation cohort. (TIF 869 KB)

262_2023_3453_MOESM2_ESM.tif

Supplementary Figure S2. Survival outcomes on the basis of baseline MCP-1, MIP-1β, or PDGF-AB/BB status in the discovery cohort. a Kaplan–Meier survival curves for PFS (left) and OS (right) on the basis of MCP-1 status (log-rank, P = 0.013 for PFS and P = 0.11 for OS). b Kaplan–Meier survival curves for PFS (left) and OS (right) on the basis of MIP-1β status (log-rank, P = 0.0035 for PFS and P = 0.42 for OS). c Kaplan–Meier survival curves for PFS (left) and OS (right) on the basis of PDGF-AB/BB status (log-rank, P = 0.016 for PFS and P = 0.41 for OS). MCP-1, monocyte chemoattractant protein-1; MIP-1β, macrophage inflammatory protein-1β; OS, overall survival; PDGF-AB/BB, platelet-derived growth factor-AB/BB; PFS, progression-free survival. (TIF 1303 KB)

262_2023_3453_MOESM3_ESM.tif

Supplementary Figure S3. Progression-free survival on the basis of baseline MCP-1 (a), MIP-1β (b), or PDGF-AB/BB (c) status in the validation cohort. P values were calculated by the log-rank test. (TIF 690 KB)

262_2023_3453_MOESM4_ESM.tif

Supplementary Figure S4. Patient and tumor characteristics on the basis of baseline IL-6 and IL-15 status in the merged cohort. a Proportion of patients who ever smoked or never smoked on the basis of IL-6 and IL-15 levels classified as both low, either high, or both high. P value was calculated by the Fisher exact test. b Proportion of patients with PD-L1 expression of ≥50% or <50% on the basis of IL-6 and IL-15 levels classified as both low, either high, or both high. P value was calculated by the Fisher exact test. c Proportion of patients harboring tumors with EGFR mutations or without on the basis of IL-6 and IL-15 levels classified as both low, either high, or both high. P value was calculated by the Fisher exact test. Among the patients in the merged cohort (N = 220), information regarding PD-L1 expression and EGFR mutations was available in 205 and 176 patients, respectively. EGFR, epidermal growth factor receptor; PD-L1, programmed death-ligand 1. (TIF 700 KB)

Supplementary file5 (DOCX 21 KB)

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Inoue, Y., Inui, N., Karayama, M. et al. Cytokine profiling identifies circulating IL-6 and IL-15 as prognostic stratifiers in patients with non-small cell lung cancer receiving anti-PD-1/PD-L1 blockade therapy. Cancer Immunol Immunother 72, 2717–2728 (2023). https://doi.org/10.1007/s00262-023-03453-z

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