Immune Escape Mechanisms in Colorectal Cancer Pathogenesis and Liver Metastasis
Figure 3
NT5E/CD73 facilitates escape from immune-surveillance and orchestrates the tumour-stroma interplay to promote cancer growth and metastasis. (a) Representative images of NT5E/CD73 immunostaining in a primary carcinoma and corresponding liver metastasis. White and black arrows indicate the immunostaining in the stromal compartment and malignant colonic cells, respectively, magnification 10X. (b) NT5E/CD73 immunostaining is higher in liver metastatic tissues than in primary tumours or normal colonic mucosa and significantly correlates with CD68 infiltration. NT5E/CD73 expression is not correlated with the MMR status in our cohort of CRC patients. (c) Schematic drawing of the proposed mechanism(s) involved in metastasis-promoting actions of NT5E/CD73. In physiological conditions, NT5E/CD73 hydrolyzes AMP to adenosine, an important mediator that binds A2A receptors on activated CD4 effector T-cells, decreasing their proliferation and cytokine production, hence mediating immunosuppressive effects. NT5E/CD73 is expressed in a variety of stromal cells (macrophages, endothelial cells, B-lymphocytes, and Treg-cells). A variety of oncogenic pathways can induce ectopic NT5E/CD73 expression in CRC cells, enhancing paracrine/autocrine interactions (activation of A2B receptors) between malignant colonic, hematopoietic, and nonhematopoietic cells to sustain immunosurveillance escape and cancer cell migration. PPAR (peroxisome proliferator-activated receptor gamma) has been suggested as a possible NT5E/CD73 antagonist through still unknown mechanisms. IE: intraepithelial; IM: invasive margin; Liv Met: liver metastases; MMR pro and MMR neg indicate MMR proficient and deficient tumours, respectively. The value is reported in each graph.
