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Endocrine

P28: Single-cell imaging mass cytometry identifies phenotypic subsets of Gastroenteropancreatic Neuroendocrine Tumors

Introduction:

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.

Learning Objectives:

  • Participants will develop a global understanding of how P-NETs and SB-NETs' prognosis and management is guided by the disease grade, stage, and underlying pathobiology.
  • Participants will understand the role of tumor-associated macrophages (TAMs) in inhibiting the adaptive immune response, stimulating fibrosis, and supporting invasive phenotypes for GEP-NET tumor microenvironment.
  • Participates will be able to describe the technique of imaging mass cytometry, cell clustering and neighborhood profiling.