Cerebrospinal Fluid Immunological Cytokines Predict Intracranial Tumor Response to Immunotherapy in Non-small Cell Lung Cancer Patients with Brain Metastases

Overview

Journal Oncoimmunology

Specialty Allergy & Immunology

Date 2024 Jan 3

PMID 38169917

Authors

Meichen Li

Jing Chen

Hui Yu

Baishen Zhang

Xue Hou

Honghua Jiang

Dan Xie

Likun Chen

Affiliations

Soon will be listed here.

Abstract

Background: Immunotherapy has shown intracranial efficacy in non-small cell lung cancer (NSCLC) patients with brain metastases. However, predictive biomarkers for intracranial response to immunotherapy are lacking. This post-hoc analysis aimed to explore the potential of immunological cytokines in cerebrospinal fluid (CSF) to predict intracranial tumor response to immunotherapy in patients with brain metastases.

Methods: Treatment-naive NSCLC patients with brain metastases who received camrelizumab plus chemotherapy were enrolled. Paired plasma and CSF samples were prospectively collected at baseline and the first treatment assessment. All samples were analyzed for 92 immuno-oncology cytokines using Olink's panels.

Results: A total of 28 patients were included in this analysis. At baseline, most immunological cytokines were significantly lower in CSF than in plasma, whereas a subset comprising CD83, PTN, TNFRSF21, TWEAK, ICOSLG, DCN, IL-8, and MCP-1, was increased in CSF. Baseline CSF levels of LAMP3 were significantly higher in patients with intracranial tumor response, while the levels of CXCL10, IL-12, CXCL11, IL-18, TIE2, HGF, and PDCD1 were significantly lower. Furthermore, the CXCL10, CXCL11, TIE2, PDCD1, IL-18, HGF, and LAMP3 in CSF were also significantly associated with intracranial progression-free survival for immunotherapy. The identified cytokines in CSF were decreased at the first treatment evaluation in patients with intracranial tumor response. The logistic CSF immuno-cytokine model yielded an AUC of 0.91, as compared to PD-L1 expression (AUC of 0.72).

Conclusions: Immunological cytokines in CSF could predict intracranial tumor response to immunotherapy in NSCLC patients with brain metastases, and the findings warrant validation in a larger prospective cohort study.

Trial Registration: ClinicalTrials.gov identifier: NCT04211090.

References

Mansfield A, Aubry M, Moser J, Harrington S, Dronca R, Park S . Temporal and spatial discordance of programmed cell death-ligand 1 expression and lymphocyte tumor infiltration between paired primary lesions and brain metastases in lung cancer. Ann Oncol. 2016; 27(10):1953-8. PMC: 5035793. DOI: 10.1093/annonc/mdw289. View

Wang M, Xie Z, Xu J, Feng Z . TWEAK/Fn14 axis in respiratory diseases. Clin Chim Acta. 2020; 509:139-148. DOI: 10.1016/j.cca.2020.06.007. View

De Marchi P, Leal L, da Silva V, da Silva E, Cordeiro de Lima V, Reis R . PD-L1 expression by Tumor Proportion Score (TPS) and Combined Positive Score (CPS) are similar in non-small cell lung cancer (NSCLC). J Clin Pathol. 2021; 74(11):735-740. DOI: 10.1136/jclinpath-2020-206832. View

Ulas E, Hashemi S, Houda I, Kaynak A, Veltman J, Fransen M . Predictive Value of Combined Positive Score and Tumor Proportion Score for Immunotherapy Response in Advanced NSCLC. JTO Clin Res Rep. 2023; 4(9):100532. PMC: 10480627. DOI: 10.1016/j.jtocrr.2023.100532. View

Rubio-Perez C, Planas-Rigol E, Trincado J, Bonfill-Teixidor E, Arias A, Marchese D . Immune cell profiling of the cerebrospinal fluid enables the characterization of the brain metastasis microenvironment. Nat Commun. 2021; 12(1):1503. PMC: 7940606. DOI: 10.1038/s41467-021-21789-x. View

Zaitseva O, Hoffmann A, Otto C, Wajant H . Targeting fibroblast growth factor (FGF)-inducible 14 (Fn14) for tumor therapy. Front Pharmacol. 2022; 13:935086. PMC: 9634131. DOI: 10.3389/fphar.2022.935086. View

Liu Y, He S, Wang X, Peng W, Chen Q, Chi D . Tumour heterogeneity and intercellular networks of nasopharyngeal carcinoma at single cell resolution. Nat Commun. 2021; 12(1):741. PMC: 7854640. DOI: 10.1038/s41467-021-21043-4. View

Kudo Y, Haymaker C, Reuben A, Duose D, Fujimoto J, Roy-Chowdhuri S . Suppressed immune microenvironment and repertoire in brain metastases from patients with resected non-small-cell lung cancer. Ann Oncol. 2019; 30(9):1521-1530. PMC: 6771224. DOI: 10.1093/annonc/mdz207. View

Palma G, Barbieri A, Bimonte S, Palla M, Zappavigna S, Caraglia M . Interleukin 18: friend or foe in cancer. Biochim Biophys Acta. 2013; 1836(2):296-303. DOI: 10.1016/j.bbcan.2013.09.001. View

10.

Yang R, Hung M . The role of T-cell immunoglobulin mucin-3 and its ligand galectin-9 in antitumor immunity and cancer immunotherapy. Sci China Life Sci. 2017; 60(10):1058-1064. DOI: 10.1007/s11427-017-9176-7. View

11.

Ma J, Huang L, Gao Y, Li M, Chen L, Yang L . M2 macrophage facilitated angiogenesis in cutaneous squamous cell carcinoma via circ_TNFRSF21/miR-3619-5p/ROCK axis. Kaohsiung J Med Sci. 2022; 38(8):761-771. DOI: 10.1002/kjm2.12555. View

12.

Assarsson E, Lundberg M, Holmquist G, Bjorkesten J, Thorsen S, Ekman D . Homogenous 96-plex PEA immunoassay exhibiting high sensitivity, specificity, and excellent scalability. PLoS One. 2014; 9(4):e95192. PMC: 3995906. DOI: 10.1371/journal.pone.0095192. View

13.

De Mattos-Arruda L, Mayor R, Ng C, Weigelt B, Martinez-Ricarte F, Torrejon D . Cerebrospinal fluid-derived circulating tumour DNA better represents the genomic alterations of brain tumours than plasma. Nat Commun. 2015; 6:8839. PMC: 5426516. DOI: 10.1038/ncomms9839. View

14.

Borghaei H, Ciuleanu T, Lee J, Pluzanski A, Caro R, Gutierrez M . Long-term survival with first-line nivolumab plus ipilimumab in patients with advanced non-small-cell lung cancer: a pooled analysis. Ann Oncol. 2022; 34(2):173-185. DOI: 10.1016/j.annonc.2022.11.006. View

15.

Lv Y, Ma X, Ma Y, Du Y, Feng J . A new emerging target in cancer immunotherapy: Galectin-9 (LGALS9). Genes Dis. 2023; 10(6):2366-2382. PMC: 10404877. DOI: 10.1016/j.gendis.2022.05.020. View

16.

Iwata R, Lee J, Hayashi M, Dianzani U, Ofune K, Maruyama M . ICOSLG-mediated regulatory T-cell expansion and IL-10 production promote progression of glioblastoma. Neuro Oncol. 2019; 22(3):333-344. PMC: 7442411. DOI: 10.1093/neuonc/noz204. View

17.

Cheng S, Li Z, Gao R, Xing B, Gao Y, Yang Y . A pan-cancer single-cell transcriptional atlas of tumor infiltrating myeloid cells. Cell. 2021; 184(3):792-809.e23. DOI: 10.1016/j.cell.2021.01.010. View

18.

Alessandrini F, Pezze L, Ciribilli Y . LAMPs: Shedding light on cancer biology. Semin Oncol. 2018; 44(4):239-253. DOI: 10.1053/j.seminoncol.2017.10.013. View

19.

Baker K, Houston A, Brint E . IL-1 Family Members in Cancer; Two Sides to Every Story. Front Immunol. 2019; 10:1197. PMC: 6567883. DOI: 10.3389/fimmu.2019.01197. View

20.

El-Deeb M, Gaber El-Sheredy H, Mohammed A . The Possible Role of Interleukin (IL)-18 and Nitrous Oxide and Their Relation to Oxidative Stress in the Development and Progression of Breast Cancer. Asian Pac J Cancer Prev. 2019; 20(9):2659-2665. PMC: 6976825. DOI: 10.31557/APJCP.2019.20.9.2659. View