PD-1 blockade enhances chemotherapy toxicity in oesophageal adenocarcinoma.

Autor: Davern M; Cancer Immunology and Immunotherapy Group, Department of Surgery, Trinity Translational Medicine Institute and Trinity St. James's Cancer Institute, St. James's Hospital, Trinity College Dublin, Dublin 8, Ireland., O' Brien RM; Translational Radiobiology and Diagnostics Group, Department of Surgery, Trinity Translational Medicine Institute, St. James's Hospital, Dublin 8, Ireland., McGrath J; Translational Radiobiology and Diagnostics Group, Department of Surgery, Trinity Translational Medicine Institute, St. James's Hospital, Dublin 8, Ireland., Donlon NE; Cancer Immunology and Immunotherapy Group, Department of Surgery, Trinity Translational Medicine Institute and Trinity St. James's Cancer Institute, St. James's Hospital, Trinity College Dublin, Dublin 8, Ireland., Melo AM; Cancer Immunology and Immunotherapy Group, Department of Surgery, Trinity Translational Medicine Institute and Trinity St. James's Cancer Institute, St. James's Hospital, Trinity College Dublin, Dublin 8, Ireland., Buckley CE; Translational Radiobiology and Diagnostics Group, Department of Surgery, Trinity Translational Medicine Institute, St. James's Hospital, Dublin 8, Ireland., Sheppard AD; Cancer Immunology and Immunotherapy Group, Department of Surgery, Trinity Translational Medicine Institute and Trinity St. James's Cancer Institute, St. James's Hospital, Trinity College Dublin, Dublin 8, Ireland., Reynolds JV; Department of Surgery, Trinity Translational Medicine Institute, St. James's Hospital, Trinity College Dublin, Dublin 8, Ireland., Lynam-Lennon N; Translational Radiobiology and Diagnostics Group, Department of Surgery, Trinity Translational Medicine Institute, St. James's Hospital, Dublin 8, Ireland., Maher SG; Cancer Chemoradiation Group, Department of Surgery, Trinity Translational Medicine Institute, St. James's Hospital, Dublin 8, Ireland., Lysaght J; Cancer Immunology and Immunotherapy Group, Department of Surgery, Trinity Translational Medicine Institute and Trinity St. James's Cancer Institute, St. James's Hospital, Trinity College Dublin, Dublin 8, Ireland. jlysaght@tcd.ie.
Jazyk: angličtina
Zdroj: Scientific reports [Sci Rep] 2022 Feb 28; Vol. 12 (1), pp. 3259. Date of Electronic Publication: 2022 Feb 28.
DOI: 10.1038/s41598-022-07228-x
Abstrakt: Chemotherapy upregulates immune checkpoint (IC) expression on the surface of tumour cells and IC-intrinsic signalling confers a survival advantage against chemotherapy in several cancer-types including oesophageal adenocarcinoma (OAC). However, the signalling pathways mediating chemotherapy-induced IC upregulation and the mechanisms employed by ICs to protect OAC cells against chemotherapy remain unknown. Longitudinal profiling revealed that FLOT-induced IC upregulation on OE33 OAC cells was sustained for up to 3 weeks post-treatment, returning to baseline upon complete tumour cell recovery. Pro-survival MEK signalling mediated FLOT-induced upregulation of PD-L1, TIM-3, LAG-3 and A2aR on OAC cells promoting a more immune-resistant phenotype. Single agent PD-1, PD-L1 and A2aR blockade decreased OAC cell viability, proliferation and mediated apoptosis. Mechanistic insights demonstrated that blockade of the PD-1 axis decreased stem-like marker ALDH and expression of DNA repair genes. Importantly, combining single agent PD-1, PD-L1 and A2aR blockade with FLOT enhanced cytotoxicity in OAC cells. These findings reveal novel mechanistic insights into the immune-independent functions of IC-intrinsic signalling in OAC cells with important clinical implications for boosting the efficacy of the first-line FLOT chemotherapy regimen in OAC in combination with ICB, to not only boost anti-tumour immunity but also to suppress IC-mediated promotion of key hallmarks of cancer that drive tumour progression.
(© 2022. The Author(s).)
Databáze: MEDLINE
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