Immune landscape of small intestinal neuroendocrine tumor at single-cell level (A12)

Introduction: Small intestinal neuroendocrine tumor (SI-NET) is the most common malignant tumor of the small intestine. Despite its prominence, a full understanding of the immune landscape in SI-NET remains elusive.

Aim(s): We aim to delve into the immune atlas of SI-NET and unravel the mechanisms contributing to the limited immunotherapy efficacy in SI-NET.

Materials and methods: Five matched samples underwent single-cell RNA sequencing (scRNA), which was complemented by integrating one publicly available SI-NET scRNA data. Immunohistochemistry staining was performed for validation.

Results: Following quality filtering, 22,482 immune cells were included. T and NK cells were divided into 17 subgroups, B cells into 4, and myeloid cells into 10. Within the tumor, CD4 T cells, B cells, mast cells and macrophages were significantly enriched, while NK cells, CD8 T cells, DC, neutrophils, and monocytes were notably deficient. The cytotoxic pathways were diminished in intra-tumoral CD4 and CD8 T cells. TCR analysis revealed significantly less clonal expansion of T cells within the tumor compared to those outside, suggesting insufficient activation. Endothelial cells (EC) and perivascular cells (PVL) enriched within the tumor exhibited significantly elevated expression of TGFB1. Among the intra-tumoral immune cells, CD8 T cells were most responsive to TGFB1 according to Cytosig analysis. EC and PVL might inhibit the activation of CD8 T cells through TGFB1-TGFBR1 interaction. Intra-tumoral macrophages exhibited an M2 phenotype, while B cells showed no significant distinctions between tumors and non-tumor tissues.

Conclusion: SI-NET manifests an immunosuppressive landscape wherein TGFB1 secreted by EC and PVL within tumor may play a crucial role.

Keywords: small intestinal neuroendocrine tumor, single-cell rna sequencing, immunosuppressive, cd8 t cells, tgfb1