Objectives: Despite the great progression made in current immunotherapy against malignancies, the immune environment and its potential for neuroendocrine neoplasms (NENs) to respond to immune checkpoint inhibitors remain largely unexplored. To evaluate the immune-based therapeutic strategy for pancreatic neuroendocrine tumors, we assessed B7 checkpoint inhibitors expression, lymphocytic infiltration, and associated prognostic profiles in a large cohort of pancreatic NENs.
Methods: Full B7 protein family checkpoint inhibitors, including B7-1, B7-2, B7h, B7-H3, B7x, HHLA2, PD-L1, PD-L2, and B7-H6 were examined for expression through immunohistochemistry staining of tissue microarrays containing 146 primary pancreatic neuroendocrine tumors and 5 metastatic tumors. Additionally, the immune-microenvironmental response was accessed by detection of macrophages, functional NK cells, CD3+, CD4+, and CD8+ T cells infiltration. Finally, each checkpoint inhibitor’s prognostic roles as well as the clinical manifestations were analyzed.
Results: In overview, B7h, B7-H3, HHLA2, PD-L1, and PD-L2 were absent in pancreatic neuroendocrine neoplasms, whereas the expression of B7-1 (63/146, 44.06%), B7-2 (137/146, 93.84%), B7x (75/146, 51.37%), and B7-H6 (126/146, 86.30%) were common. B7-H3 was only expressed in stroma cells (141/146, 96.58%). For the local immune response aspect, tumor-associated macrophages (13/146, 8.9%), CD3+ (6/146, 4.11%) and CD4+ (14/146, 9.59%) T cells were negative in most PanNENs tissues, whereas CD8+ T cells were positive in nearly half of the cases (66/146, 45.20%) and significantly associated with worse post-surgical overall survival rates. For subgroup analysis, there is no significant relationship between PanNENs staging or the post-surgical overall survival rates with the B7 protein antigens expression. By comparison between primary PanNEN tissues with limited metastatic PanNEN tissues, elevated B7-H6 expression was observed. Interestingly, B7-H6 expression was significantly associated with PanNENs post-surgically recurrence.
Conclusions: Our findings provided a comprehensive profiling of the immune environment of PanNENs. Among the B7 antigens, upregulated B7-H6 expression indicates a relatively high risk of recurrence in PanNENs patients. There is a certain extent of infiltrated CD8+ T cells in PanNEN tissues, which also predicts a worse prognosis. Overall, B7-1, B7-2, B7x, and B7-H6 were potential immunotherapeutic targets for further molecular biological and mechanism research in the future.