Abstract 3134: Pilot study of immune status of GEP-NETs in tumor microenvironment
Authors: Ichikawa Yasushi , Kobayashi Noritoshi , Goto Ayumu , Tokuhisa Motohiko , Hiroshima Yukihiko , Ishikawa Takashi , Takano Shoko , Inoue Tomio , Endo Itaru 
Published: August 2018

Abstract
Introduction: Neuroendocrine tumor (NET) is a rare cancer, however, morbidity rate is increasing every year. Recently, effective molecular targeting drugs for NET were developed and leading acceptable results, however, it is still not enough. Immune checkpoint inhibitor is becoming a very effective drug in malignant melanoma, lung cancer, and some kind of cancer showing microsatellite instability (MSI).
Aim: Aim of this study is to investigate NET about MSI status and immune status of microenvironment using NET patients' operative or biopsy samples.
Method: Patients were 20 NETs, male: 11, female: 9, G1: 6, G2: 8, G3: 6, pancreas: 11, duodenum: 4, colon: 2, liver: 1, unknown: 2. Using patients' samples by operative resection or biopsy, examinations by immunohistochemistry were performed to confirm MSI status using MSH2, MSH6, PMS2 and MLH1 antibody and count the cell number expressing PD-L1, PD-1, CD8 or Foxp3. Expression of MSH2, MSH6, PMS2, MLH1 and PD-L1 was evaluated on tumor cells. Specimens were categorized as IHC negative or positive if &lt; 1% or &gt; 1% of cells were stained by each monoclonal antibody. Expression of PD-1, CD8, Foxp3 was evaluated on the infiltrating lymphocyte of intratumor and peritumor respectively. Positive cells absolute number of each staining were counted in the 3 hot spot field (X400) and then the average of the 3 field of each specimen was utilized.
Results: MSI: Expression of the 4 mismatch repair protein could be detected in the all 20 NETs tumor, then there was no case showing MSI. PD-L1 was detected in the 15 cases (75%). PD-L1 was expressed in the surface of tumors. PD-1 was also detected 15 cases (75%). PD-1 was expressed in the surface of infiltrative intratumoral and peritumoral lymphocyte. Both of PD-L1 in the tumor and PD-1 in the lymphocyte were detected in the 12 cases (60%). PD-L1 was detected in 72.7% of pancreatic NET, 72% of gastroenteral NET. PD-L1 was detected in 100% of NET-G1, 75% of G2 and 50% of G3. The absolute number of intratumoral PD-1+ lymphocyte, CD8+ lymphocyte or Foxp3+ lymphocyte was higher in the PD-L1+ tumor than in the PD-L1- tumor. In peritumor, there was not a similar tendency. In the PD-L1 positive NET, the absolute number of intratumoral PD-1+ lymphocyte or CD8+ lymphocyte increased according to NET grade.
Conclusion: Seventy-five% of GEP-NET expressed PD-L1. It might be higher rate of PD-L1 expression compared with other cancers. The absolute number of Intratumoral infiltrating lymphocyte expressing PD-1 or CD8 was also high. There might be a fraction of a good target for immune check point therapy in NETs.
Citation Format: Yasushi Ichikawa, Noritoshi Kobayashi, Ayumu Goto, Motohiko Tokuhisa, Yukihiko Hiroshima, Takashi Ishikawa, Shoko Takano, Tomio Inoue, Itaru Endo. Pilot study of immune status of GEP-NETs in tumor microenvironment [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 3134.