1496P - Higher levels of CSF-1 support resistance to immune checkpoint inhibitors in advanced non-small cell lung cancer

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.