PURPOSE: To understand prognostic immune cell infiltration signatures in neuroendocrine neoplasms (NENs), particularly pheochromocytoma and paraganglioma (PCPG), we analyzed tumor transcriptomic data from The Cancer Genome Atlas (TCGA) and other published tumor transcriptomic data of NENs. METHODS: We used CIBERSORT to infer immune cell infiltrations from bulk tumor transcriptomic data from PCPGs, in comparison to gastroenteropancreatic neuroendocrine tumors (GEPNETs) and small cell lung carcinomas (SCLCs). PCPG immune signature was validated with NanoString immune panel in an independent cohort. Unsupervised clustering of the immune infiltration scores from CIBERSORT was used to find immune clusters. A prognostic immune score model for PCPGs and the other NENs were calculated as a linear combination of the estimated infiltration of activated CD8+/CD4+ T cells, activated NK cells, and M0 and M2 macrophages. RESULTS: In PCPGs, we found five dominant immune clusters, associated with M2 macrophages, monocytes, activated NK cells, M0 macrophages and regulatory T cells, and CD8+/CD4+ T cells respectively. Non-metastatic tumors were associated with activated NK cells and metastatic tumors were associated with M0 macrophages and regulatory T cells. In GEPNETs and SCLCs, M0 macrophages and regulatory T cells were associated with unfavorable outcomes and features, such as metastasis and high-grade tumors. The prognostic immune score model for PCPGs and the NENs could predict non-aggressive and non-metastatic diseases. In PCPGs, the immune score was also an independent predictor of metastasis-free survival in a multivariate Cox regression analysis. CONCLUSION: The transcriptomic immune signature in PCPG correlates with clinical features like metastasis and prognosis.

Department of Medical Biology Faculty of Science University of South Bohemia Ceske Budejovice 37005 Czech Republic

Department of Medical Sciences Uppsala University Akademiska Sjukhuset ing 78 75185 Uppsala Sweden

Department of Nuclear Medicine La Timone University Hospital Aix Marseille University Marseille France

European Center for Research in Medical Imaging Aix Marseille University Marseille France

Office of Surgeon Scientists Programs Center for Cancer Research National Cancer Institute National Institutes of Health Bethesda MD 20892 USA

Radiation Oncology Branch Center for Cancer Research National Cancer Institute National Institutes of Health Bethesda MD 20892 USA

Section on Medical Neuroendocrinology Eunice Kennedy Shriver National Institute of Child Health and Human Development National Institutes of Health Bethesda MD 20892 USA

Surgical Oncology Program Center for Cancer Research National Cancer Institute National Institutes of Health Bethesda MD 20892 USA

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