title: Identification of immunotherapeutic targets by genomic profiling of rectal NET metastases.
abstract: Neuroendocrine tumors (NETs) of the gastrointestinal tract are a rare and heterogeneous group of neoplasms with unique tumor biology and clinical management issues. While surgery is the only curative treatment option in patients with early stage NETs, the optimal management strategy for patients with advanced metastatic NETs is unknown. Based on the tremendous success of immunotherapeutic approaches, we sought to investigate such approaches in a case of metastatic rectal NET. Here, we apply an integrative approach using various computational and experimental methods to explore several aspects of the tumor-host immune interactions for immunotherapeutic options. Sequencing of six different liver metastases revealed a quite homogenous set of mutations, and further analysis of these mutations for immunogenicity revealed few neo-epitopes with pre-existing T cell reactivity, which can be used in therapeutic vaccines. Staining for immunomodulatory proteins and cytokine profiling showed that the immune setting is surprisingly different, when compared to liver metastases of colorectal cancer for instance. Taken together, our results highlight the broad range and complexity of tumor-host immune interaction and underline the value of an integrative approach.
authors.affiliation: Clinical Cooperation Unit "Applied Tumor Immunity", National Center for Tumor Diseases (NCT) and German Cancer Research Center (DKFZ), Heidelberg, Germany; Department of Medical Oncology, National Center for Tumor Diseases (NCT) and University Hospital Heidelberg, Heidelberg, Germany.
authors.forename: Zeynep
authors.initials: Z
authors.lastname: Koşaloğlu
authors.affiliation: Department of Medical Oncology, National Center for Tumor Diseases (NCT) and University Hospital Heidelberg , Heidelberg, Germany.
authors.forename: Inka
authors.initials: I
authors.lastname: Zörnig
authors.affiliation: Department of Medical Oncology, National Center for Tumor Diseases (NCT) and University Hospital Heidelberg , Heidelberg, Germany.
authors.forename: Niels
authors.initials: N
authors.lastname: Halama
authors.affiliation: Department of Medical Oncology, National Center for Tumor Diseases (NCT) and University Hospital Heidelberg , Heidelberg, Germany.
authors.forename: Iris
authors.initials: I
authors.lastname: Kaiser
authors.affiliation: Division of Theoretical Bioinformatics (B080), German Cancer Research Center (DKFZ) , Heidelberg, Germany.
authors.forename: Ivo
authors.initials: I
authors.lastname: Buchhalter
authors.affiliation: Department of Medical Oncology, National Center for Tumor Diseases (NCT) and University Hospital Heidelberg , Heidelberg, Germany.
authors.forename: Niels
authors.initials: N
authors.lastname: Grabe
authors.affiliation: Division of Theoretical Bioinformatics (B080), German Cancer Research Center (DKFZ), Heidelberg, Germany; Department for Bioinformatics and Functional Genomics, Institute for Pharmacy and Molecular Biotechnology (IPMB) and BioQuant, Heidelberg University, Heidelberg, Germany.
authors.forename: Roland
authors.initials: R
authors.lastname: Eils
authors.affiliation: Division of Theoretical Bioinformatics (B080), German Cancer Research Center (DKFZ) , Heidelberg, Germany.
authors.forename: Matthias
authors.initials: M
authors.lastname: Schlesner
authors.affiliation: Department of Biomedical Informatics, Department of Systems Biology, Center for Computational Biology and Bioinformatics, Herbert Irving Comprehensive Cancer Center, Columbia University , New York, NY, USA.
authors.forename: Andrea
authors.initials: A
authors.lastname: Califano
authors.affiliation: Clinical Cooperation Unit "Applied Tumor Immunity", National Center for Tumor Diseases (NCT) and German Cancer Research Center (DKFZ), Heidelberg, Germany; Department of Medical Oncology, National Center for Tumor Diseases (NCT) and University Hospital Heidelberg, Heidelberg, Germany.
authors.forename: Dirk
authors.initials: D
authors.lastname: Jäger
keywords: Cytokines; IHC; immunotherapy; neo-epitopes; neoantigens; tumor immunology; tumor microenvironment; vaccination