Longitudinal immune monitoring of patients with resectable esophageal adenocarcinoma treated with Neoadjuvant PD-L1 checkpoint inhibition.

The analysis of peripheral blood mononuclear cells (PBMCs) by flow cytometry holds promise as a platform for immune checkpoint inhibition (ICI) biomarker identification. Our aim was to characterize the systemic immune compartment in resectable esophageal adenocarcinoma patients treated with neoadjuvant ICI therapy. In total, 24 patients treated with neoadjuvant chemoradiotherapy (nCRT) and anti-PD-L1 (atezolizumab) from the PERFECT study (NCT03087864) were included and 26 patients from a previously published nCRT cohort. Blood samples were collected at baseline, on-treatment, before and after surgery. Response groups for comparison were defined as pathological complete responders (pCR) or patients with pathological residual disease (non-pCR). Based on multicolor flow cytometry of PBMCs, an immunosuppressive phenotype was observed in the non-pCR group of the PERFECT cohort, characterized by a higher percentage of regulatory T cells (Tregs), intermediate monocytes, and a lower percentage of type-2 conventional dendritic cells. A further increase in activated Tregs was observed in non-pCR patients on-treatment. These findings were not associated with a poor response in the nCRT cohort. At baseline, immunosuppressive cytokines were elevated in the non-pCR group of the PERFECT study. The suppressive subsets correlated at baseline with a Wnt/β-Catenin gene expression signature and on-treatment with epithelial-mesenchymal transition and angiogenesis signatures from tumor biopsies. After surgery monocyte activation (CD40), low CD8+Ki67+ T cell rates, and the enrichment of CD206+ monocytes were related to early recurrence. These findings highlight systemic barriers to effective ICI and the need for optimized treatment regimens.
Competing Interests: MIvBH is consultant for Mylan, Johnson & Johnson, Alesi Surgical, BBraun and Medtronic, and received unrestricted research grants from Stryker. All fees paid to institution. NHM has served as a consultant for MSD, BMS, Astra Zeneca, Servier and Lilly. MFB received research funding from Celgene and Lead Pharma and has acted as a consultant for Servier. HWMvL: Consultant or advisory role: BMS, Daiichy, Dragonfly, Eli Lilly, MSD, Nordic Pharma, Servier. Research funding and/or medication supply: Bayer, BMS, Celgene, Janssen, Incyte, Eli Lilly, MSD, Nordic Pharma, Philips, Roche, Servier. Speaker role: Astellas, Daiichy, Novartis. TDdG reports to be in an advisory role for GE Healthcare, Mendus and LAVA Therapeutics, to have received a research grant from Idera Pharmaceuticals, and to be co-founder and owner of stocks of LAVA Therapeutics, outside of the submitted work. The other authors report no conflict of interest.
(© 2023 The Author(s). Published with license by Taylor & Francis Group, LLC.)