Abstract CT208: High tumor monocyte content predicts long-term survival for patients with operable oesophageal cancer treated with neoadjuvant immunochemotherapy in the LUD2015-005 trial
Authors: Fuchs Hannah S. , James Sabrina A. , Carroll Thomas M. , Xie Phil F. , Chadwick Joseph A. , Parkes Duncan , Lord Simon R. , Griffiths Lucinda , Underwood Tim , Karydis Ioannis , Petty Russell T. , Schuster-Böckler Benjamin , Owen Richard P. , Middleton Mark R. , Lu Xin 
Published: April 2024

Background: Combined immune checkpoint inhibitors (ICI) with chemotherapy in advanced oesophageal cancer (OC) has shown survival benefit in phase III studies, resulting in ICI’s recent approval to treat advanced OC. The role of ICI in peri-operative OC is debated, and large clinical studies are ongoing. Patients’ response to immunochemotherapy is highly variable and it is unclear what underlies this heterogeneity. To address this challenge, 38 advanced and 35 operable OC patients were enrolled to receive ICI in the LUD2015-005 trial (NCT02735239).

Methods: We investigated the clinical and biological effects of adding the anti-PD-L1 ICI durvalumab to peri-operative chemotherapy or chemoradiotherapy (CRT) in a phase II multicentre study (LUD2015-005 trial). Operable OC patients received ICI for four weeks, followed by combination treatment with ICI + chemotherapy (oxaliplatin and capecitabine or fluorouracil, leucovorin, oxaliplatin, and docetaxel (FLOT)), or ICI + CRT (CROSS regimen). Patients could also receive ICI for up to 6 months after surgery. Tissue samples were collected at baseline, after four weeks ICI-only, and on the day of surgery. Further to assessing synergy of ICI with standard peri-operative treatment for OC, our trial design enables an in-depth analysis of molecular features of response, and to dissect the impact of ICI alone on the tumor microenvironment. Single cell and bulk transcriptomic data were generated and used to perform RNA deconvolution to estimate tumor cell composition.

Results: The treatment was well-tolerated and two-year survival was 80% and 73.3% with ICI + chemotherapy and ICI + CRT, respectively. Survival was superior to that of propensity score matched patients receiving standard of care (p = 0.047). Tumor cell composition analysis revealed that neither total T-cell numbers nor a specific T-cell functional phenotype was associated with outcome, but high tumor monocyte content (TMC) at baseline was highly predictive of overall survival (p = 0.003). Moreover, a 13-gene core monocyte gene signature was sufficient to predict overall survival (p = 0.022) and major pathological response (mPR, Mandard 1-2, p = 0.009). Patients with mPR at resection showed enrichment of interferon and IL15 signalling at the four-week ICI-only timepoint (p &lt; 0.001). Single cell trajectory interference combined with immune response enrichment analysis also show that high interferon and IL15 signalling drive monocytes to differentiate into M1 macrophages and dendritic cells.

Conclusion: Similar to our previous finding in immunochemotherapy treated advanced OC patients (Carroll et al. Cancer Cell 2023), TMC is a highly predictive biomarker of long-term survival for operable OC patients treated with neoadjuvant immunochemotherapy, highlighting the importance of tumor monocytes and their differentiation potential in OC patients’ response to ICI.

Citation Format: Hannah S. Fuchs, Sabrina A. James, Thomas M. Carroll, Phil F. Xie, Joseph A. Chadwick, Duncan Parkes, Simon R. Lord, Lucinda Griffiths, Tim Underwood, Ioannis Karydis, Russell T. Petty, Benjamin Schuster-Böckler, Richard P. Owen, Mark R. Middleton, Xin Lu. High tumor monocyte content predicts long-term survival for patients with operable oesophageal cancer treated with neoadjuvant immunochemotherapy in the LUD2015-005 trial [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 2 (Late-Breaking, Clinical Trial, and Invited Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(7_Suppl):Abstract nr CT208.