Nutrient deprivation and hypoxia alter T cell immune checkpoint expression: potential impact for immunotherapy

• DOI: 10.1007/s00432-022-04440-0
• Publication Date: 2022-11-29T14:03:46Z
• Authors: Maria Davern; Noel E. Donlon; Fiona O’Connell; Caoimhe Gaughan; Cillian O’Donovan; Jason McGrath; Andrew D. Sheppard; Conall Hayes; Ross King; Hugo Temperley; Michael MacLean; Christine Bulter; Anshul Bhardwaj; Jenny Moore; Claire Donohoe; Narayanasamy Ravi; Melissa J. Conroy; John V. Reynolds; Joanne Lysaght
• Keywords: Immune checkpoint; TIGIT

Use of immune checkpoint blockade to enhance T cell-mediated immunity within the hostile tumour microenvironment (TME) is an attractive approach in oesophageal adenocarcinoma (OAC). This study explored effects TME, including nutrient deprivation and hypoxia, on (IC) expression cell phenotypes, potential use nivolumab function under such conditions.ICs were upregulated stromal cells PD-L2, CTLA-4 TIGIT. OAC patient-derived PBMCs co-cultured with OE33 LAG-3 downregulated co-stimulatory marker CD27 cells, highlighting direct immunosuppressive cells. Hypoxia altered secretome PBMCs, which induced upregulation PD-L1 PD-L2 thus enhancing immune-resistant phenotype. Importantly, culturing dual hypoxia glucose deprivation, reflective conditions array ICs surface PD-1, CTLA-4, A2aR, decreased IFN-γ by Addition these production pro-tumorigenic cytokine IL-10.Collectively, findings highlight crosstalk between TME. The ability suppress phenotypes TME supports a rationale for promote anti-tumour OAC. Study schematic: (A) IC profiles assessed CD45+ peripheral whole blood infiltrating tissue from patients treatment-naïve setting. (B) isolated expanded ex vivo 5 days using anti-CD3/28 + IL-2 activation protocol then 48 h flow cytometry. (C) further cultured or cytometry.(A) TIGIT, correlated subsequent response neoadjuvant regimen. Following co-culture marker. Nutrient range Nivolumab IL-10 deprivation-hypoxic conditions.