Background: Immunotherapy is currently being explored in many tumour types with encouraging results, but has not yet been evaluated in neuroendocrine tumours (NET). Our aim is to characterise the immune landscape of NET and determine which immune-modulatory pathways control the tumour infiltrating lymphocytes (TILs) in order to develop a rational approach for immunotherapy in this tumour type.
Methods: Peripheral blood and fresh tissue was obtained from consenting patients with midgut NET, and subjected to multicolour flow-cytometry to determine the abundance of CD8+, CD4+FoxP3- effector (CD4eff) and CD4+FoxP3+ regulatory (Treg) T cell subsets and the expression of co-inhibitory and co-stimulatory checkpoint molecules on these subsets. Additionally, matched FFPE tissue was obtained for multiparametric immunohistochemistry to investigate the distribution of the immune infiltrate.
Results: Tissue from 31 midgut NET patients (20: G1 and 11: G2) was analysed. Overall the tumours contained a higher proportion of Tregs compared with matched healthy tissue with an effector (CD8+ and CD4eff) to Treg ratio of 18.1:24.3 respectively (P=0.0004). The co-inhibitory molecules CTLA-4, PD-1, and TIM-3 showed highest expression on Tregs, while LAG-3 expression was similar across all T cell subsets. Co-stimulatory molecules, including ICOS, 41BB and OX-40, were also highest on Tregs, as was the recently identified co-stimulatory receptor TIGIT. Immunohistochemistry revealed that the majority of cases have <1% intratumoural CD4+ and CD8+T cells but a higher number of peritumoural T cells from all subsets. Where present, T cells were predominantly CD8+ and intratumoural CD163+ macrophages were also identified.
Conclusion: These preliminary results provide novel insight into the immune landscape of NET, and may inform the development of targeted combination immunotherapies. Initial results suggest that checkpoint molecules, such as CTLA-4 and PD-1, may be potential targets in this tumour type and work is ongoing to further elucidate the immunogenic potential of NET.
04 Dec 2017
UK and Ireland Neuroendocrine Tumour Society