Tumor Microenvironment in Mixed Neuroendocrine Non-Neuroendocrine Neoplasms: Interaction between Tumors and Immune Cells, and Potential Effects of Neuroendocrine Differentiation on the Tumor Microenvironment

Simple Summary The neuroendocrine differentiation of tumors is considered to influence the tumor microenvironment through the secretion of various hormones or growth factors. However, cases of neuroendocrine and non-neuroendocrine neoplasms are difficult to compare because of the potential differences in systemic and local immune environments. The analysis of mixed neuroendocrine non-neuroendocrine neoplasms, in which neuroendocrine and non-neuroendocrine components are present in the same tumor, could provide important insights into the effects of neuroendocrine differentiation on tumor microenvironments. However, to the best of our knowledge, this has not been reported yet. Here, we compared the status of the tumor tissue microenvironment, including the infiltrating lymphocytes present, in the neuroendocrine and non-neuroendocrine areas of the same tumor. Factors related to neoangiogenesis and the suppression of tumor immune reactions were more abundant in neuroendocrine than in non-neuroendocrine areas. Therefore, neuroendocrine and non-neuroendocrine tumors differ with respect to the characteristics of both tumor cells and the tumor microenvironment. Abstract The tumor microenvironment is considered to play a pivotal role in various human malignancies. Neuroendocrine and non-neuroendocrine neoplasms are considered to have different tumor microenvironments. However, owing to differences in the systemic and/or local immune statuses, tumor microenvironments in different patients may be difficult to compare. Mixed neuroendocrine non-neuroendocrine neoplasms (MiNENs), although rare, could be useful for exploring the effects of neuroendocrine differentiation on the tumor microenvironment, because both neuroendocrine and non-neuroendocrine components are present in the same tumor. Here, we examined 33 cases of histologically confirmed MiNENs and evaluated the influence of neuroendocrine differentiation on the tumor microenvironment by comparing tumor-infiltrating lymphocytes, tumor-associated macrophages, and other relevant factors in the two components the same tumor. The immunoreactivity of those examined above was evaluated quantitatively. The values of vasohibin-1-positive density (p < 0.0001) and immunoreactivity (p < 0.0001) (representing the neoangiogenesis status) were significantly higher in neuroendocrine as compared to non-neuroendocrine areas of the same tumors. In addition, the Foxp3/CD8 (p = 0.0717) and the PD-1/CD8 ratios (p = 0.0176) (representing tumor immunity suppression) tend to increase in neuroendocrine carcinomas. Immunoreactivity of CD163, a marker of M2-like macrophages, was also higher in the neuroendocrine areas. Our findings indicate that neuroendocrine and non-neuroendocrine tumors differ from each other with respect to the characteristics of both tumor cells and the tumor microenvironment.