The Roles of Immune Cells Derived from Clonal Hematopoiesis in Colorectal Cancer Metastasis

[Backgrounds] Clonal hematopoiesis (CH) has been observed in over 20% of patients diagnosed with solid cancers, and it has been associated with a poor prognosis in most cases, with the exception of colorectal cancer (CRC) patients who tend to have a favorable prognosis. Among the various gene mutations detected in CH, TET2 mutations are particularly prevalent. Previous research has demonstrated that the impact of TET2-mutated CH immune cells depends on the specific types of cancer tissues involved. Specifically, studies have shown that Tet2-KO myeloid cells can inhibit the progression of melanoma while promoting the growth of hepatoma and lung cancers. However, there is a limited understanding of the roles of TET2-mutated CH immune cells on CRC progression. [ Methods] We conducted an experiment focusing on CRC and CH using CRC organoid cells transplanted into the spleens of different types of Tet2 conditional knockout mice: VAV1Cre (with Tet2 gene deletion in all hematopoietic cells), LysMCre (myeloid cells), CD19Cre (B lymphocytes), and CD4Cre (T lymphocytes). After a period of 30 days, we collected livers for analysis. The extent of liver metastasis tumor burden (LMTB) was determined by counting the number of tumor foci on 10 hematoxylin-stained slides, with an interval of 80 μm between each slide. We utilized immunohistochemistry (IHC) and flow cytometry (FC) to analyze immune cells. The number of positive cells was automatically counted in 10 fields at 20x magnification. Furthermore, we performed whole transcriptome analysis (WTA) on sorted CD4+, CD8+, CD11b+, and CD19+ cells, respectively. [Results] LMTB was significantly lower in VAV1Cre and CD4Cre mice compared to the control mice ( VAV1Cre vs. control: 55.65±35.62 vs. 89.93±34.57 foci/1000 mm², p