1499P - Wnt5-ROR2 signalling mediated resistance to immune checkpoint inhibitors in advanced non-small cell lung cancer

Background

Emerging evidence suggests that Beta-catenin-independent Wnt signaling is upregulated in lung carcinogenesis, but few studies have investigated its prognostic value or its impact on the immune response in NSCLC patients undergoing checkpoint inhibitors (ICIs therapy. The goal of this study is to examine the prognostic significance of non-canonical Wnt signaling molecules, and their potential value as drug targets to enhance the efficacy of ICIs in NSCLC patients.

Methods

This study enrolled a prospective cohort of 52 patients with advanced NSCLC receiving immune checkpoint inhibitors (ICIs) therapy. Samples (plasma and lung biopsies) were collected at various stages of treatment and analysed for Wnt expression using RT-qPCR, flow cytometry, ELISA assays, and immunohistochemistry. To investigate the mechanism of Wnt-mediated drug response, including response to ICIs and/or chemotherapy, stimulated PBMCs (anti-CD3/CD28 + rh-IL2) were treated with or without pembrolizumab and cultured/co-cultured with recombinant Wnt5a,Wnt inhibitors and NSCLC explants.

Results

We found higher levels of Wnt5a and Wnt5b in patient’s samples. Wnt5a was upregulated in patients’ plasma compared to healthy donors (1262 vs 372.0 ± pg/mL, p < 0.001). Samples collected at first evaluation had low levels of Wnt5a compared to the baseline (1262 vs 771.9 pg/mL, p < 0.01). Wnt5a expression was related with poor therapy response (RR =2.4; p = 0,05) and shorter survivals (PFS non reached vs 259 days, HR =0.141, p < 0.01). ELISA analysis of supernatants from NSCLC cell culture showed that supporting the fact that Wnt5a and Wnt5b are produced by tumor cells. In vito experiments demonstrated that recombinant Wnt5a as well as NSCLC monolayer, suppressed lymphocytes activation and the production of INF γ. These effects were reverted by Wnt inhibitors, including porcupine inhibitors.

Conclusions

The preclinical results of our study provide comprehensive validation for the modulation of Wnt as a drug candidate to improve the effectiveness of immunotherapy in treating NSCLC. Our findings offer compelling evidence that Wnt5 signalling can serve as predictive biomarkers and drug targets to prevent disease relapse in advanced NSCLC patients receiving ICIs.

Clinical trial identification

Editorial acknowledgement

Legal entity responsible for the study

Université Paris Saclay/UVSQ.

Funding

Ligue Contre le Cancer (2022).

Disclosure

E. Giroux-Leprieur: Financial Interests, Personal, Advisory Role: Amgen, AstraZeneca, Ipsen, Janssen, Lilly, MSD, Novartis, Pfizer, Sanofi, Takeda. All other authors have declared no conflicts of interest.