Busse Antonia, Mochmann Liliana H, Spenke Christiane, Arsenic Ruza, Briest Franziska, Jöhrens Korinna, Lammert Hedwig, Sipos Bence, Kühl Anja A, Wirtz Ralph, Pavel Marianne, Hummel Michael, Kaemmerer Daniel, Baum Richard P, Grabowski Patricia
Department of Hematology, Oncology and Tumor Immunology, Campus Benjamin Franklin, Charité-Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin, Humboldt-Universität zu Berlin and Berlin Institute of Health, 12203 Berlin, Germany.
German Cancer Consortium (DKTK), Partner Site Berlin and German Cancer Research Center (DKFZ), 69120 Heidelberg, Germany.
Cancers (Basel). 2020 Nov 19;12(11):3448. doi: 10.3390/cancers12113448.
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 IFNγ 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.
检查点抑制剂在多种肿瘤中已显示出有前景的结果；然而，在神经内分泌肿瘤（NET）和神经内分泌癌（NEC）中，报告的缓解率较低。我们在此旨在研究NET/NEC中的肿瘤免疫微环境，以确定程序性细胞死亡蛋白1（PD-1）/程序性死亡配体1（PD-L1）等检查点通路是否可能在免疫逃逸中起作用，以及是否需要靶向其他逃逸机制以实现有效的抗肿瘤反应。通过免疫组织化学（IHC）和包括数字空间分析在内的mRNA免疫分析对48例NET和30例NEC样本进行了分析。通过IHC，NET/NEC均显示出基质中CD3+ T细胞浸润，但肿瘤内浸润较少，尽管NEC中的浸润明显高于NET。免疫细胞上PD1、PD-L1和含T细胞免疫球蛋白和粘蛋白结构域蛋白3（TIM3）的表达较低或几乎不存在。mRNA免疫分析显示NET和NEC中IFNγ诱导基因的表达较低，且无任何空间异质性。然而，我们观察到趋化因子的mRNA表达增加，趋化因子可吸引NET和NEC中的髓样细胞，以及与免疫抑制性髓样细胞相关的基因和具有免疫抑制功能的基因（如CD47和CD74）丰度较高。总之，NET和NEC缺乏适应性免疫系统激活的迹象，而是显示出几种免疫抑制基因的丰度较高，这些基因是免疫调节的潜在靶点。
