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Abstract
Background 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. We aim to explore the immune atlas of SI-NET and unravel the mechanisms contributing to the limited immunotherapy efficacy in SI-NET.
Methods Five matched samples underwent single-cell RNA sequencing (scRNA-seq), complemented by integrating five publicly available SI-NET scRNA-seq data (IDDF2024-ABS-0120 Figure 1 (A)).
Results T and NK cells were divided into 16 subgroups, B cells into 3, and myeloid cells into 8 (IDDF2024-ABS-0120 Figure 1 (B-D)). Within the primary tumor, B cells, mast cells, CD4 T cells, plasma cells and macrophages were significantly enriched, while NK cells, CD8 T cells, neutrophils and monocytes were notably deficient. Within the liver metastasis tumor, NK cells, dendritic cells (DC) and macrophages were significantly enriched (IDDF2024-ABS-0120 Figure 2 (A)). The cytotoxic pathways were diminished in intra-tumoral CD4 and CD8 T cells. Compared to the adjacent non-tumor tissues, the proportion of T cells with a single clonal T cell receptor (TCR) type was higher within the tumor, and the diversity of TCRs was greater within the primary tumor compared to adjacent tissue (IDDF2024-ABS-0120 Figure 2 (B)). This suggested that TCR expansion was less common within the tumor, and there were fewer activated T cells within the tumor compared to the adjacent tissue. Endothelial cells (EC) and perivascular-like cells (PVL) enriched within the primary tumor exhibited significantly elevated expression of TGFB1. Among the intra-tumoral immune cells, CD8 T cells were most responsive to TGFB1(IDDF2024-ABS-0120 Figure 2 (C)). EC and PVL might inhibit the activation of CD8 T cells through TGFB1-TGFBR1 interaction. The dysfunction of T cells within liver metastasis tumor may be attributed to a large number of DC with low expression of co-stimulatory genes (IDDF2024-ABS-0120 Figure 2 (D)).
Conclusions Our analysis reveals distinct immunosuppressive microenvironments in primary SINET tumors and liver metastases. In primary tumors, it may be TGFB1 released by EC and PVL, while in liver metastases, the presence of DC with low expression of co-stimulatory molecules may contribute to T cell dysfunction.