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. 2024 Dec 2:15:1480183.
doi: 10.3389/fimmu.2024.1480183. eCollection 2024.

Serum cytokines as a biomarker for immune checkpoint inhibitor toxicity in patients with pleural mesothelioma

Saima Jamil Farooqi  1   2 , Zhi Zhao  3 , Åsa Kristina Öjlert  1   2 , Solfrid Thunold  1   2 , Hedvig Vidarsdotter Juul  4 , Maria Moksnes Bjaanæs  1 , Henrik Horndalsveen  1   2 , Hanne Marte Gjertsen Nymoen  2 , Åslaug Helland  1   2   5 , Vilde Drageset Haakensen  1   2   5
Affiliations

Serum cytokines as a biomarker for immune checkpoint inhibitor toxicity in patients with pleural mesothelioma

Saima Jamil Farooqi et al. Front Immunol. .

Abstract

Background: Pleural mesothelioma (PM) is a rare cancer with a dismal prognosis. Dual immune checkpoint inhibitors have improved overall survival, but the rate of immune-related adverse events (irAEs) is high. Serum cytokines reflect systemic immune reactions and may serve as biomarkers for irAEs.

Patients and methods: Patients with pleural mesothelioma treated with nivolumab and ipilimumab with or without UV1 vaccine in the NIPU study were included. Serum cytokine levels were measured by Bio-Plex Pro Human Cytokine Screening 48-Plex Panel Assay. Correlations between cytokine levels and irAEs were analyzed by generalized linear mixed models to identify potential diagnostic and predictive biomarkers.

Results: Higher levels of MIG, eotaxin, MIP-1α, IP-10, TNF-α, MIP-1β, IL-4, MIF, IL-16, IL-2RA, SCGF.β and PDFG-BB at baseline are associated with increased risk of developing one or more irAEs. In particular, higher baseline levels of MIG are positively associated with thyroiditis and hypophysitis, and elevated levels of IP-10 and MIG to dermatitis. During the course of treatment, higher levels of MIG, eotaxin, MIF, TNF-α, MIP-1β, IL-4 and IL-16 are associated with an ongoing irAE. We found both predictive and diagnostic value of MIF with fatigue and of eotaxin with both colitis and pneumonitis. Higher levels of CTACK is associated with a lower risk of developing hepatitis, both before and after treatment.

Conclusions: Elevated levels of certain cytokines, both before and after onset of treatment, correlate with specific irAEs in PM patients receiving ICIs. These cytokines may be used as biomarkers to predict and detect irAES.

Keywords: biomarkers; checkpoint inhibition blockade; cytokines; immunotherapy; pleural mesothelioma.

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Conflict of interest statement

The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

Figures

Figure 1
Figure 1
Distribution of various irAEs by grade, with the Y-axis representing the number of irAEs and the X-axis showing the irAE types.
Figure 2
Figure 2
Associations between baseline cytokine levels and future development of irAEs. Each figure panel shows the effect of the identified cytokine. The height of a bar is the conditional ME of the identified cytokine and the corresponding error bar shows the SD of the cytokine’s effect. A positive ME indicates that high baseline level is associated with increased risk of developing the irAE, while a negative value suggests a protective association.
Figure 3
Figure 3
Association between cytokine level and ongoing irAEs. Each figure panel shows the conditional ME and SD of the identified Cytokine: Time interaction corresponding to an irAE. Association is drawn if the absolute ME of a Cytokine: Time interaction is larger than its corresponding SD.
Figure 4
Figure 4
Effect of prednisolone treatment on cytokine levels in various irAEs. An association is significant if the ME of the cytokine exceeds its corresponding SD. A positive ME indicates that prednisolone results in a further increase in the specific cytokine compared to patients who are not receiving prednisolone for the particular irAE.
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References

    1. Baas P, Scherpereel A, Nowak AK, Fujimoto N, Peters S, Tsao AS, et al. . First-line nivolumab plus ipilimumab in unresectable Malignant pleural mesothelioma (CheckMate 743): a multicentre, randomised, open-label, phase 3 trial. Lancet. (2021) 397:375–86. doi: 10.1016/S0140-6736(20)32714-8 - DOI - PubMed
    1. Peters S, Scherpereel A, Cornelissen R, Oulkhouir Y, Greillier L, Kaplan MA, et al. . First-line nivolumab plus ipilimumab versus chemotherapy in patients with unresectable Malignant pleural mesothelioma: 3-year outcomes from CheckMate 743. Ann Oncol. (2022) 33:488–99. doi: 10.1016/j.annonc.2022.01.074 - DOI - PubMed
    1. Aamdal E, Inderberg EM, Ellingsen EB, Rasch W, Brunsvig PF, Aamdal S, et al. . Combining a universal telomerase based cancer vaccine with ipilimumab in patients with metastatic melanoma - five-year follow up of a phase I/IIa trial. Front Immunol. (2021) 12:663865. doi: 10.3389/fimmu.2021.663865 - DOI - PMC - PubMed
    1. Brunsvig PF, Guren TK, Nyakas M, Steinfeldt-Reisse CH, Rasch W, Kyte JA, et al. . Long-term outcomes of a phase I study with UV1, a second generation telomerase based vaccine, in patients with advanced non-small cell lung cancer. Front Immunol. (2020) 11:572172. doi: 10.3389/fimmu.2020.572172 - DOI - PMC - PubMed
    1. Wang M, Zhai X, Li J, Guan J, Xu S, Li Y, et al. . The role of cytokines in predicting the response and adverse events related to immune checkpoint inhibitors. Front Immunol. (2021) 12:670391. doi: 10.3389/fimmu.2021.670391 - DOI - PMC - PubMed

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