PS02.124: NOVEL APPROACHES AND CONSIDERATIONS FOR IMMUNOTHERAPY IN OBESITY-ASSOCIATED OESOPHAGEAL ADENOCARCINOMA

Abstract

Abstract Background Immunotherapies are transforming cancer treatment for inoperable and advanced disease. However, the incidence of obesity-associated cancers, including oesophageal adenocarcinoma (OAC) continue to increase. Treatment with immune-based therapies present a unique challenge for immunologists, as they need to enhance anti-tumour immunity without exacerbating pre-existing carcinogenic inflammation. Therefore, we examined the effect of PD-1 blockade in omentum and liver of OAC patients, sites of activated inflammatory T cells, which play a key role in obesity-associated inflammation. In addition, we examined novel ways to reduce the infiltration of inflammatory T cells to these sites in a bid to reduce adipose tissue inflammation. Methods Blood, omentum and liver samples were obtained from consenting OAC patients and treated with anti-PD-1 antibody. CD4+ and CD8+ T cell activation, cytokine expression and cytotoxic potential were assessed by flow cytometry. To identify potential chemokine pathways to alter T cell trafficking to the omentum and liver, chemokine receptor expression was examined, along with levels of secreted chemokines using flow cytometry and ELISAs. Pre-treatment of T cells with chemokine receptor antagonists was performed prior to chemotaxis assays using an in vitro transwell system. Results In addition to OAC tumour, 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 did not enhance inflammatory cytokine expression or proliferation, but transiently increased CD107a expression by CD8+ T cells. MIP-1α, MIP-1β and IP-10 mediate T cell trafficking to the omentum and liver in OAC. OAC-derived T cells preferentially migrate to the adipose and liver tissue conditioned media of obese OAC patients and this can be significantly reduced using a MIP-1α receptor antagonist. Conclusion This study provides evidence that anti-PD-1 treatment is unlikely to exacerbate pre-existing T cell-mediated inflammation outside the tumour in obesity-associated cancers. Furthermore, novel CCR1 antagonists may be used to attenuate pathological inflammation in obesity. This dual targeting approach aims to enhance anti-tumour immunity through the use of immune checkpoint inhibitors, and has identified a novel immunotherapeutic approach to reduce obesity-associated inflammation by targeting key chemokine pathways. In vivo testing is required to determine the efficacy of this approach. Disclosure All authors have declared no conflicts of interest.