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Characterization of the Neuroendocrine Tumor Immune Microenvironment

da Silva, Annacarolina, MD*†; Bowden, Michaela, PhD*; Zhang, Sui, PhD*; Masugi, Yohei, MD, PhD*; Thorner, Aaron R., PhD; Herbert, Zachary T., MS§; Zhou, Chensheng Willa, MS*; Brais, Lauren, MPH*; Chan, Jennifer A., MD*; Hodi, F. Stephen, MD*; Rodig, Scott, MD, PhD; Ogino, Shuji, MD, PhD†∥; Kulke, Matthew H., MD

doi: 10.1097/MPA.0000000000001150
Original Articles

Objectives The immune environment and the potential for neuroendocrine tumors (NETs) to respond to immune checkpoint inhibitors remain largely unexplored. We assessed immune checkpoint marker expression, lymphocytic infiltrate, and associated mutational profiles in a cohort of small intestine and pancreatic NETs.

Methods We assessed expression of PDCD1 (PD-1), CD274 (PD-L1), and PDCD1LG2 (PD-L2) in archival tissue from 64 small intestine (SINETs) and 31 pancreatic NETs (pNET). We additionally assessed T-cell infiltrates, categorizing T-cell subsets based on expression of the T-cell markers CD3, CD8, CD45RO (PTPRC), or FOXP3. Finally, we explored associations between immune checkpoint marker expression, lymphocytic infiltrate, and tumor mutational profiles.

Results Expression of PD-1 or PD-L1 in small intestine or pancreatic NET was rare, whereas expression of PD-L2 was common in both NET subtypes. T-cell infiltrates were more abundant in pNET than in SINET. We found no clear associations between immune checkpoint marker expression, immune infiltrates, and specific mutational profile within each tumor type.

Conclusions Our findings provide an initial assessment of the immune environment of well-differentiated NETs. Further studies to define the immunologic differences between pNET and SINET, as well as the role of PD-L2 in these tumors, are warranted.

From the *Department of Medical Oncology, Dana-Farber Cancer Institute;

Department of Pathology, Brigham and Women's Hospital;

Center for Cancer Genome Discovery,

§Molecular Biology Core Facilities, and

Department of Pathology, Dana-Farber Cancer Institute; and

Department of Epidemiology, Harvard TH Chan School of Public Health, Boston, MA.

Received for publication January 25, 2018; accepted July 14, 2018.

Address correspondence to: Matthew H. Kulke, MD, Section of Hematology and Oncology, Boston University and Boston Medical Center, 820 Harrison Ave, Boston MA 02118 (e-mail:

The authors declare no conflict of interest.

This study was supported in part by a grant from the NET Research Foundation to M.H.K. This study was also supported by US National Institutes of Health (NIH) grants R01 CA151532 to M.H.K., R01 CA151993 to S.O., and R35 CA197735 to S.O.

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