Extratumoral PD-1 blockade does not perpetuate obesity-associated inflammation in esophageal adenocarcinoma. (1st April 2018)

• Record Type: Journal Article
• Authors: Galvin, Karen C.; Conroy, Melissa J.; Doyle, Suzanne L.; Dunne, Margaret R.; Fahey, Ronan; Foley, Emma; O'Sullivan, Katie E.; Doherty, Derek G.; Geoghegan, Justin G.; Ravi, Narayanasamy; O'Farrelly, Cliona; Reynolds, John V.; Lysaght, Joanne
• Is Part Of: Cancer letters. Volume 418(2018)
• Page Start: 230
• Page End: 238
• Publication Date: 2018-04-01
• Subjects: Cancer -- PD-1 -- Immunotherapy -- Inflammation -- T cells -- Esophageal adenocarcinoma; Cancer -- Periodicals; Neoplasms -- Periodicals; Cancer -- Périodiques; Electronic journals; 616.994
• DOI: 10.1016/j.canlet.2018.01.039
• Languages: English
• ISSNs: 0304-3835

Abstract

Abstract: Checkpoint inhibitors, such as anti-PD-1 (Programmed death-1), are transforming cancer treatment for inoperable or advanced disease. As the incidence of obesity-associated malignancies, including esophageal adenocarcinoma (EAC) continues to increase and treatment with checkpoint inhibitors are being FDA approved for a broader range of cancers, it is important to assess how anti-PD-1 treatment might exacerbate pre-existing inflammatory processes at other sites. Outside the EAC tumor, the omentum and liver were found to be enriched with substantial populations of PD-1 expressing T cells. Treatment of omental and hepatic T cells with anti-PD-1 (clone EH12.2H7) did not enhance inflammatory cytokine expression or proliferation, but transiently increased CD107a expression by CD8 + T cells. Importantly, PD-1-expressing T cells are significantly lower in EAC tumor post neoadjuvant chemoradiotherapy, suggesting that combination with specific conventional treatments may severely impair the efficacy of anti-PD-1 immunotherapy. This study provides evidence that systemically administered anti-PD-1 treatment is unlikely to exacerbate pre-existing T cell-mediated inflammation outside the tumor in obesity-associated cancers, such as EAC. Furthermore, our data suggests that studies are required to identify the negative impact of concomitant therapies on PD-1 expression in order to boost overall response rates. Highlights: PD-1 + T cells are enriched in the omentum, liver and tumor of EAC patients. Anti-PD-1 does not enhance T cell mediated inflammation in omentum or liver. Blocking PD-1 temporarily restores CD8 + T cell cytotoxic potential. Intratumoral PD-1 expression is significantly reduced following chemoradiotherapy.