Correlation of Neuroendocrine Differentiation with a Distinctively Suppressive Immune Microenvironment in Gastric Cancer

<b><i>Introduction:</i></b> Neuroendocrine neoplasms (NENs) harbored significantly suppressive tumor immune microenvironments (TIMEs). However, the immunological effects of neuroendocrine differentiation (NED) on non-NENs, such as gastric cancer (GC), were unknown. <b><i>Methods:</i></b> Between pure gastric cancer (PGC) and GC-NED, TIME features were scored based on expression data and validated on serial whole-tissue sections of surgical samples, with tertiary lymphoid structures (TLSs) and the extra-TLS zone evaluated independently using multi-marker immunohistochemical staining. Risk analyses of TIME features on tumor behaviors were performed in GC-NED. The universal immunological effects of NED were explored preliminarily in adenocarcinomas arising in other organs. <b><i>Results:</i></b> Based on over 11,500 annotated TLSs and 2,700 extra-TLS zones, compared with PGC, GC-NED harbored a distinctively more suppressive TIME characterized by increased but immature TLSs, with higher naïve B-cell and follicular regulatory T-cell densities and downregulated TLS maturation-related cell ratios inside TLSs; increased naïve B-cell and regulatory T-cell densities; and a high proportion of exhausted T cells in the extra-TLS zone. The upregulated tumor PD-L1 expression and its close correlations with TLS formation and maturation were remarkable exclusively in GC-NED. TIME features, especially those regarding TLSs, were significantly correlated with tumor growth and invasion. The desynchrony between TLS formation and maturation and increased naïve or regulatory immune cell infiltration was observed in adenocarcinomas of the colorectum, pancreas, lung, and prostate. <b><i>Conclusion:</i></b> NED highlighted a distinct GC entity with more suppressive TIME features correlated with tumor behaviors, indicating a cohort that would benefit more from immunotherapies.