CDX2 and SATB2 loss are associated with myeloid cell infiltration and poor survival in colorectal cancer

Background: Caudal-type homeobox 2 (CDX2) and special AT-rich sequence-binding protein 2 (SATB2) are transcription factors playing important roles in intestinal homeostasis and participating in the regulation of intestinal inflammation. In colorectal cancer (CRC), reduced expression levels of CDX2 and SATB2 have been associated with poor differentiation and worse survival. However, their prognostic significance still needs further clarification, and the associations between CDX2 and SATB2 and immune cell infiltration into the CRC microenvironment are largely unknown. Methods: We analyzed CDX2 and SATB2 expression in two large cohorts of stages I–IV CRC patients (N = 2302) and analyzed their associations with clinicopathologic parameters, the density of local immune cells (determined with three multiplex immunohistochemistry panels and conventional immunohistochemistry), and survival. Results: In mismatch repair-proficient tumors, reduced CDX2 and SATB2 expression were associated with higher densities of immature monocytic cells, macrophages, and M2-like macrophages. Low expression of CDX2 was associated with shorter cancer-specific survival independent of conventional prognostic parameters in both cohorts. In the larger cohort, adjusted hazard ratio (HR) for negative (vs. high) CDX2 expression was 3.62 (95% CI 2.08–6.31, p_trend < 0.0001), and adjusted HR for negative (vs. high) SATB2 level was 1.61 (95% CI 0.97–2.67, p_trend= 0.002). Conclusion: This study indicates that reduced CDX2 and SATB2 expression levels are associated with myeloid cell infiltration in the CRC microenvironment and represent markers for poor outcome. These findings highlight the potential of CDX2 and SATB2 as biomarkers for classifying CRC patients and support their role in regulating the tumor microenvironment.