PD-1 and TIGIT blockade differentially affect tumour cell survival under hypoxia and glucose deprived conditions in oesophageal adenocarcinoma; implications for overcoming resistance to PD-1 blockade in hypoxic tumours

• DOI: 10.1016/j.tranon.2022.101381
• Publication Date: 2022-03-01T17:42:33Z
• Authors: Maria Davern; Marie-Claire Fitz...; Croí E. Buckley; Aisling B. Heeran; Noel E. Donlon; Jason McGrath; Fiona O’ Connell; Malvika R. Deshpande; Conall Hayes; Jamie MacDonald; Andrew D. Sheppard; John V. Reynolds; Stephen G. Maher; Niamh Lynam-Lennon; Brona Murphy; Joanne Lysaght
• Keywords: TIGIT; Hypoxia; Anaerobic glycolysis

Recent studies have demontrated that immune checkpoint receptors are expressed on the surface of oesophageal adenocarcinoma (OAC) cells and might confer a survival advantage. This study explores role PD-1 TIGIT signalling in OAC either promoting or inhibiting under characteristic features tumour microenvironment including nutrient-deprivation hypoxia. normal pre-malignant epithelial this expression significantly decreases along normal- Barrett's Oesophagus- disease sequence. However, glucose-deprivation hypoxia upregulated vitro. blockade decreased cell proliferation normoxia but enhanced death glucose-deprivation. induced death, an effect was maintained Basal respiration glycolytic reserve were GLUT1 subpopulation following blockade. In contrast, phenotype cells, yet other metabolic parameters oxidative phosphorylation basal respiration. Interestingly, inhibition glycolysis These findings suggest immune-independent mechanism for inhibitor resistance hypoxic tumours be more effective therapeutic target compared with treating tumours.