Endocrine
Eric Pletcher, MD
Complex General Surgical Oncology Fellow
Cedars Sinai
Los Angeles, California, United States
Eric Pletcher, MD
Complex General Surgical Oncology Fellow
Cedars Sinai
Los Angeles, California, United States
Eric Pletcher, MD
Complex General Surgical Oncology Fellow
Cedars Sinai
Los Angeles, California, United States
Simeon Mahov, M.S.
Bioinformatician
Cedars-Sinai Medical center, United States
Andrew Bellizzi, M.D,
Clinical Professor of Pathology
University of Iowa, United States
Monica Justo, M.D.
General Surgery Resident
Cedars-Sinai Medical Center, United States
Alexander Xu, PhD
Project Scientist
Cedars-Sinai Medical Center, United States
Akil Merchant, M.D.
Attending
Cedars-Sinai Medical Center, United States
James R. Howe, M.D.
Professor
University of Iowa Hospitals and Clinics
Iowa City, IA, United States
Alexandra Gangi, M.D.
Attending
Cedars-Sinai Medical Center
Los Angeles, California, United States
Epigenetic alterations in immune cells, stroma, and extracellular matrix (ECM) of Gastroenteropancreatic Neuroendocrine Tumor (GEP-NET) microenvironment (TME) may account for changes in metastasis and tumor progression. However, current management guidelines of metastatic GEP-NET do not take these molecular changes into consideration for this clinico-pathological heterogenous group. Single-cell imaging mass cytometry (IMC) can identify specific phenotypic subsets of GEP-NET and their spatial relationships within the TME to personalize prognostication and may help guide future immune-directed therapy.
Methods:
Twenty-four patients with metastatic ileal (n = 13) and pancreatic (n = 11) GEP-NETs were included and tissue microarrays were created. Overall (OS) and progression-free survival (PFS) were also recorded. IMC was used to simultaneously quantify protein expression using a metal-tagged antibody panel (n = 42) to identify tumor, stromal, and immune phenotypes within small bowel and pancreatic GEP-NET at the primary tumor, lymph nodes and sites of metastases. Phenotypic densities at tumor rich sites were correlated with PFS and OS.
Results:
Spatial proteogenomic TME analysis revealed 12 distinct cellular clusters and 12 cellular neighborhoods. (Figure 1) Increased phenotypic density of cancer-associated fibroblasts (CAF) in PNET liver metastasis were significantly associated with PFS, versus CD4 cell and M1 macrophage infiltration for SB-NET. (p < 0.05) Additionally, plasmacytoid dendritic cells (pDC) at the site of PNET lymph node metastasis were associated with OS. (p = 0.02)
Conclusions:
Single-cell IMC characterizes the GEP-NET TME profile specifically with respect to immune and stromal subsets and their spatial relationships. M1 macrophage and CD4 cell infiltration in SB-NET and CAF density within liver metastasis for PNET were associated with PFS. To our knowledge, this is the first report to utilize single-cell IMC to characterize the GEP-NET TME at single-cell spatial resolution across primary tumor and multiple metastatic sites.