PMID- 33228231 OWN - NLM STAT- PubMed-not-MEDLINE LR - 20240330 IS - 2072-6694 (Print) IS - 2072-6694 (Electronic) IS - 2072-6694 (Linking) VI - 12 IP - 11 DP - 2020 Nov 19 TI - Immunoprofiling in Neuroendocrine Neoplasms Unveil Immunosuppressive Microenvironment. LID - 10.3390/cancers12113448 [doi] LID - 3448 AB - Checkpoint inhibitors have shown promising results in a variety of tumors; however, in neuroendocrine tumors (NET) and neuroendocrine carcinomas (NEC), low response rates were reported. We aimed herein to investigate the tumor immune microenvironment in NET/NEC to determine whether checkpoint pathways like programmed cell death protein 1 (PD-1)/programmed death-ligand 1 (PD-L1) might play a role in immune escape and whether other escape mechanisms might need to be targeted to enable a functional antitumor response. Forty-eight NET and thirty NEC samples were analyzed by immunohistochemistry (IHC) and mRNA immunoprofiling including digital spatial profiling. Through IHC, both NET/NEC showed stromal, but less intratumoral CD3+ T cell infiltration, although this was significantly higher in NEC compared to NET. Expression of PD1, PD-L1, and T cell immunoglobulin and mucin domain-containing protein 3 (TIM3) on immune cells was low or nearly absent. mRNA immunoprofiling revealed low expression of IFNgamma inducible genes in NET and NEC without any spatial heterogeneity. However, we observed an increased mRNA expression of chemokines, which attract myeloid cells in NET and NEC, and a high abundance of genes related to immunosuppressive myeloid cells and genes with immunosuppressive functions like CD47 and CD74. In conclusion, NET and NEC lack signs of an activation of the adaptive immune system, but rather show abundance of several immunosuppressive genes that represent potential targets for immunomodulation. FAU - Busse, Antonia AU - Busse A AUID- ORCID: 0000-0002-3470-6947 AD - Department of Hematology, Oncology and Tumor Immunology, Campus Benjamin Franklin, Charite-Universitatsmedizin Berlin, Corporate Member of Freie Universitat Berlin, Humboldt-Universitat zu Berlin and Berlin Institute of Health, 12203 Berlin, Germany. AD - German Cancer Consortium (DKTK), Partner Site Berlin and German Cancer Research Center (DKFZ), 69120 Heidelberg, Germany. FAU - Mochmann, Liliana H AU - Mochmann LH AD - Department of Hematology, Oncology and Tumor Immunology, Campus Benjamin Franklin, Charite-Universitatsmedizin Berlin, Corporate Member of Freie Universitat Berlin, Humboldt-Universitat zu Berlin and Berlin Institute of Health, 12203 Berlin, Germany. FAU - Spenke, Christiane AU - Spenke C AD - Department of Hematology, Oncology and Tumor Immunology, Campus Benjamin Franklin, Charite-Universitatsmedizin Berlin, Corporate Member of Freie Universitat Berlin, Humboldt-Universitat zu Berlin and Berlin Institute of Health, 12203 Berlin, Germany. FAU - Arsenic, Ruza AU - Arsenic R AD - Institute of Pathology, Charite-Universitatsmedizin Berlin, Corporate Member of Freie Universitat Berlin Humboldt-Universitat zu Berlin and Berlin Institute of Health, 12203 Berlin, Germany. AD - Institute fur histologische und zytologische Diagnostik AG Aarau, 5000 Aarau, Switzerland. FAU - Briest, Franziska AU - Briest F AD - Department of Hematology, Oncology and Tumor Immunology, Campus Benjamin Franklin, Charite-Universitatsmedizin Berlin, Corporate Member of Freie Universitat Berlin, Humboldt-Universitat zu Berlin and Berlin Institute of Health, 12203 Berlin, Germany. FAU - Johrens, Korinna AU - Johrens K AD - Institute of Pathology, Charite-Universitatsmedizin Berlin, Corporate Member of Freie Universitat Berlin Humboldt-Universitat zu Berlin and Berlin Institute of Health, 12203 Berlin, Germany. AD - Institute of Pathology, Carl Gustav Carus University Hospital Dresden, 01307 Dresden, Germany. FAU - Lammert, Hedwig AU - Lammert H AD - Institute of Pathology, Charite-Universitatsmedizin Berlin, Corporate Member of Freie Universitat Berlin Humboldt-Universitat zu Berlin and Berlin Institute of Health, 12203 Berlin, Germany. FAU - Sipos, Bence AU - Sipos B AUID- ORCID: 0000-0002-7311-3343 AD - Department of Medical Oncology and Pneumology (Internal Medicine VIII), University Hospital Tubingen, 72076 Tubingen, Germany. AD - Private Practice of Pathology and Molecular Pathology, 70176 Stuttgart, Germany. FAU - Kuhl, Anja A AU - Kuhl AA AD - iPATH Berlin-Immunopathology for Experimental Models, Core Unit of the Charite, Charite-Universitatsmedizin Berlin, Corporate Member of Freie Universitat Berlin, Humboldt-Universitat zu Berlin, and Berlin Institute of Health, 12203 Berlin, Germany. FAU - Wirtz, Ralph AU - Wirtz R AD - Stratifyer Molecular Oncology GmbH, 50935 Cologne, Germany. FAU - Pavel, Marianne AU - Pavel M AD - Department of Endocrinology, Universitatsklinikum Erlangen, 91054 Erlangen, Germany. FAU - Hummel, Michael AU - Hummel M AD - Institute of Pathology, Charite-Universitatsmedizin Berlin, Corporate Member of Freie Universitat Berlin Humboldt-Universitat zu Berlin and Berlin Institute of Health, 12203 Berlin, Germany. AD - Central Biobank, Berlin Institute of Health, 10178 Berlin, Germany. FAU - Kaemmerer, Daniel AU - Kaemmerer D AD - Department of General and Visceral Surgery, Zentralklinik Bad Berka, 99437 Bad Berka, Germany. FAU - Baum, Richard P AU - Baum RP AD - CURANOSTICUM Wiesbaden-Frankfurt in der DKD HELIOS Klinik, 65191 Wiesbaden, Germany. FAU - Grabowski, Patricia AU - Grabowski P AD - Department of Hematology, Oncology and Tumor Immunology, Campus Benjamin Franklin, Charite-Universitatsmedizin Berlin, Corporate Member of Freie Universitat Berlin, Humboldt-Universitat zu Berlin and Berlin Institute of Health, 12203 Berlin, Germany. AD - Institute of Medical Immunology, Campus Virchow Klinikum, Charite-Universitatsmedizin Berlin, Corporate Member of Freie Universitat Berlin, Humboldt-Universitat zu Berlin and Berlin Institute of Health, 10117 Berlin, Germany. LA - eng GR - GRFF201505/Berliner Krebsgesellschaft/ GR - doctoral grant for CS/Konrad Adenauer Stiftung/ GR - investments/Sonnenfeldstiftung/ GR - consumables/THERANOSTICS RESEARCH NETWORK/ PT - Journal Article DEP - 20201119 PL - Switzerland TA - Cancers (Basel) JT - Cancers JID - 101526829 PMC - PMC7699546 OTO - NOTNLM OT - ileal neuroendocrine tumors OT - immunoprofiling OT - neuroendocrine carcinoma OT - programmed cell death protein 1 OT - programmed death-ligand 1 OT - tumor infiltrating lymphocytes OT - tumor-associated macrophages COIS- A.B. received travel grants from Daiichi Sankyo Oncology, honoraria for presentations from Hexal, Roche, and BMS and research support from Novartis and Hexal. F.B. received a travel grant and a lecture salary from Ipsen Pharma. D.K. received travel funding by the companies Ipsen, Novartis, and Pfizer. M.P. received honoraria for presentations and advisory boards from Novartis, IPSEN, Lexicon, Pfizer, AAA, and research support from IPSEN and Novartis. R.B. received consultancy fees from ITG Isotope Technologies Garching, Ipsen, Novartis, Sinotau, 3B Pharma, 1717 LSV, Shareholder of Telix Pharma, Clovis Oncology, BAMF Health. P.G. received honoraria for presentations and advisory boards from Novartis and IPSEN and research support from IPSEN and Novartis. R.W. is an employee of Stratifyer Molecular Oncology. L.M., C.S., R.A., H.T., B.S., K.J., A.A.K., and M.H. have no conflicts of interest. EDAT- 2020/11/25 06:00 MHDA- 2020/11/25 06:01 PMCR- 2020/11/19 CRDT- 2020/11/24 01:07 PHST- 2020/10/22 00:00 [received] PHST- 2020/11/12 00:00 [revised] PHST- 2020/11/16 00:00 [accepted] PHST- 2020/11/24 01:07 [entrez] PHST- 2020/11/25 06:00 [pubmed] PHST- 2020/11/25 06:01 [medline] PHST- 2020/11/19 00:00 [pmc-release] AID - cancers12113448 [pii] AID - cancers-12-03448 [pii] AID - 10.3390/cancers12113448 [doi] PST - epublish SO - Cancers (Basel). 2020 Nov 19;12(11):3448. doi: 10.3390/cancers12113448.