Heparanase (HPSE) Associates with the Tumor Immune Microenvironment in Colorectal Cancer

There is an unmet clinical need to identify potential predictive biomarkers for immunotherapy efficacy in mismatch repair proficient (pMMR) metastatic colorectal cancer (mCRC). Heparanase (HPSE) is a multifunctional molecule mediating tumor-host crosstalk. However, the function of HPSE in the tumor immune microenvironment of CRC remains unclear. Data of CRC patients from public datasets (TCGA and GSE39582) and Zhongshan Hospital (ZS cohort) were collected to perform integrative bioinformatic analyses. In total, 1036 samples from TCGA (N = 457), GSE39582 (N = 510) and ZS cohort (N = 69) were included. Samples of deficient MMR (dMMR) and consensus molecular subtypes 1 (CMS1) showed significantly higher HPSE expression. The expression of HPSE also exhibited a significantly positive association with PD-L1 expression, tumor mutation burden and the infiltration of macrophages. Immune pathways were remarkably enriched in the HPSE high-expression group, which also showed higher expressions of chemokines and immune checkpoint genes. Survival analysis suggested that high HPSE expression tended to be associated with shorter overall survival in patients with pMMR mCRC. HPSE might contribute to the immune-activated tumor microenvironment with high levels of immune checkpoint molecules, suggesting that pMMR mCRC with high HPSE expression might respond to immune checkpoint inhibitors.