Reduced resident intestinal myelomonocytic cells during ApcMin/+ mouse intestinal tumorigenesis
Session type: Poster / e-Poster / Silent Theatre session
With its significant contribution to cancer mortality globally, advanced colorectal cancer (CRC) requires new treatment strategies. However, despite recent impressive results for mismatch repair deficient (MMR-deficient) CRC and other malignancies such as melanoma, the vast majority of MMR-proficient CRCs are resistant to checkpoint inhibitor (CKI) therapy. MMR-proficient CRCs commonly develop from precursor adenomas with enhanced β-catenin signalling due to APC mutations. In melanomas with enhanced β-catenin signalling, immune anergy and resistance to CKI therapy has been observed, which is dependent on micro-environmental myelomonocytic (MM) cell depletion in melanoma models. However, MM populations of colorectal adenomas or CRC have not been studied.
To characterize resident intestinal MM cell populations during the early stages of tumorigenesis, we utilized the ApcMin/+ mouse as a model of MMR-proficient CRC, using enhanced green fuorescent protein (EGFP) expression in the M-lys lys-EGFP/+ mouse as a pan-myelomonocytic cell marker and a panel of murine macrophage surface markers.
Total intestinal lamina propria mononuclear cell (LPMNC) number decreased with age during intestinal adenoma development in ApcMin/+ mice, but not in wild-type littermates. Decreased total LPMNC numbers was associated with atrophy of intestinal lymphoid follicles and the absence of MM/lymphoid cell aggregates in ApcMin/+ mouse intestine, but not spleen, compared with wild-type mice. Furthermore, during the early stage of intestinal adenoma development, we report reduced M-lys and ER-HR3 expressing cells in mice with reduced total intestinal LPMNCs (p≤0.05).
Further studies are necessary, to determine the relevance of these findings to immune-surveillance of colorectal adenomas or MMR-proficient CRC CKI therapy resistance.