Abstract
Tumors have evolved mechanisms to escape anti-tumor immunosurveillance. They limit humoral and cellular immune activities in the stroma and render tumors resistant to immunotherapy. Sensitizing tumor cells to immune attack is an important strategy to revert immunosuppression. However, the underlying mechanisms of immune escape are still poorly understood. Here we discover Indoleamine-2,3-dioxygenase-1 (IDO1)+ Paneth cells in the stem cell niche of intestinal crypts and tumors, which promoted immune escape of colorectal cancer (CRC). Ido1 expression in Paneth cells was strictly Stat1 dependent. Loss of IDO1+ Paneth cells in murine intestinal adenomas with tumor cell-specific Stat1 deletion had profound effects on the intratumoral immune cell composition. Patient samples and TCGA expression data suggested corresponding cells in human colorectal tumors. Thus, our data uncovered an immune escape mechanism of CRC and identify IDO1+ Paneth cells as a target for immunotherapy.
Highlights
Tumors have evolved mechanisms to escape anti-tumor immunosurveillance
Enteroendocrine, Paneth, and proliferating cells in the intestinal crypts were present at normal numbers in Stat1ΔIEC ApcMin mice (Supplementary Fig. 1d-h)
We have recently shown that enhanced anti-tumor immune cell activity is reflected by increased stromal Stat[1] expression in azoxymethane-dextran sodium sulfate (AOM-DSS)-induced colorectal tumors[26]
Summary
Tumors have evolved mechanisms to escape anti-tumor immunosurveillance. They limit humoral and cellular immune activities in the stroma and render tumors resistant to immunotherapy. We discover Indoleamine-2,3-dioxygenase-1 (IDO1)+ Paneth cells in the stem cell niche of intestinal crypts and tumors, which promoted immune escape of colorectal cancer (CRC). Loss of IDO1+ Paneth cells in murine intestinal adenomas with tumor cell-specific Stat[1] deletion had profound effects on the intratumoral immune cell composition. Our data uncovered an immune escape mechanism of CRC and identify IDO1+ Paneth cells as a target for immunotherapy. We identified a subset of Paneth cells that displayed Stat1dependent expression of the immune checkpoint molecule IDO1. Loss of these cells in Stat1-deficient intestinal tumors of ApcMin mice resulted in reduced tumor load and increased infiltration of anti-tumor immune cells
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