Abstract 1496P
Background
Since the recruitment and polarization of TAMs are regulated by CSF-1R/CSF-1, the expression levels of these factors may be indicative of TAM physiology and correlated with antitumoral immunity and response to therapy. This study aimed to investigate the influence of CSF-1R/CSF-1 activation levels on tumor response in patients with advanced non-small cell lung cancer (NSCLC) receiving first-line immune checkpoint inhibitor (ICI) therapy.
Methods
This bicentric study included a prospective cohort of 88 patients with advanced NSCLC treated with ICIs as first-line therapy. Plasma levels of CSF-1 were assessed by ELISA. Peripheral blood mononuclear cells were used both for immunomodulatory assays and to produce macrophages through CSF-1 treatment. To assess the mechanism of CSF-1-mediated suppression of immunotherapy, Isolated PBMC, activated with phytohemagglutinin (PHA) with or without pembrolizumab (20 nM), were cultured alone, or in the presence of macrophages or on an established NSCLC monolayer. INFγ levels and CD8+ proliferation/activation were assessed through ELISA assay and flow cytometry respectively.
Results
Plasma levels of CSF-1 were found to be higher in patients resistant to ICI therapy (8898 vs. 14031 pg/mL, p < 0.001). Higher levels of CSF-1 were associated with poor therapy response (RR = 7,944; p = 0.013), disease progression (RR = 8.556; p < 0.001), and shorter survivals (PFS, 50 days vs. 305 days; p < 0.001; OS, 248 days vs. 1369 days, p < 0.01). In vitro, recombinant CSF-1 inhibited CD8+ activation and interferon gamma (INFγ) production that was induced by PHA and Pembrolizumab. The use of Pexidartinib (PLX-3397), a CSF-1R inhibitor, reversed the effects of CSF-1 by restoring lymphocyte activation. However, these effects were dependent on the presence of monocytes/macrophages, suggesting that the immune suppression mediated by CSF-1 was an indirect effect resulting from the stimulation of monocytes that promote their differentiation into macrophages.
Conclusions
Our study suggests that plasma levels of CSF-1 could serve as a useful predictive biomarker for resistance to ICIs, while targeting the CSF-1/CSF-1R signaling pathway could potentially overcome resistance to ICIs in patients with NSCLC.
Clinical trial identification
Legal entity responsible for the study
University of Paris Saclay, UVSQ.
Funding
Legs Poix Subvention (2018).
Disclosure
E. Giroux-Leprieur: Financial Interests, Personal, Advisory Role: Amgen, AstraZeneca, Ipsen, Janssen, Lilly, MSD, Novartis, Pfizer, Takeda, Sanofi. All other authors have declared no conflicts of interest.
Resources from the same session
1564P - Gut microbiome and metabolome are associated with the response to chemoradiotherapy in patients with esophageal cancer
Presenter: Mingqiang Lin
Session: Poster session 21
1565P - ERCC1 gene polymorphism influences overall survival in early oesophageal cancer: Results from the phase III MRC OEO2 randomised controlled trial
Presenter: Georgina Keogh
Session: Poster session 21
1566P - Clinical relevance of circulating tumor DNA in HER2 -positive advanced gastric cancer: Results from phase Ib trial of HER2 and PD-1 dual targeted therapy (Ni-High)
Presenter: Hiroki Osumi
Session: Poster session 21
1567P - The effect of SGLT2i and DPP4i on new-onset gastric cancer and gastric diseases in type 2 diabetes mellitus: A population-based cohort study
Presenter: Hou In Chou
Session: Poster session 21
1568P - Establishment of a platform to predict radiation sensitivity in organoids derived from esophageal cancer patients
Presenter: Ga Yeon Kim
Session: Poster session 21