Preclinical data implicate the ELR+ chemokine/CXCR2 axes in the pathogenesis of CCA, warranting further studies to define its role in CCA.
The prognosis of CCA remains poor, which may be partly attributable to high rates of unresectability, recurrence, and suboptimal response to standard chemotherapy, highlighting the need for novel systemic therapies. However, to further these efforts, effective preclinical models for identifying and testing new targeted or immune-based therapies are needed. At the American Society of Clinical Oncology (ASCO) 2020 Gastrointestinal Cancers Symposium, a spontaneous murine model of CCA was used to better understand the biology underlying the pathogenesis of CCA.
By histology and immunohistochemistry (IHC) staining with digital quantification performed on archival human CCA, significantly higher levels of CD15+CXCR2+ granulocytic myeloid-derived suppressor cells (G-MDSC) were found compared with adjacent normal liver (P = .0019). In addition, the CXCR2 ligand, CXCL5, was significantly elevated in CCA tumors compared with adjacent normal liver (P =.0065). These data implicate the ELR+ chemokine/CXCR2 axes in the pathogenesis of CCA to mobilize and recruit immunosuppressive G-MDSC to the tumor microenvironment.
To better understand the biology of CCA tumors, histologic and gene-expression studies were conducted in hepatic tumors grown in the spontaneous murine CCA model, which is characterized by hepatic KRAS activation and loss of p53, and normal livers from littermate controls. In addition, flow cytometric analysis was performed on bone marrow, spleen, peripheral blood from hepatic tumors, as well as controls.
In spontaneous CCA mice, quantitative real-time polymerase chain reaction tests showed a significant increase in expression of granulocyte colony-stimulating factor (CSF), CSF1, CXCL1, CXCL2, and CXCL5 (P = .0001) in the hepatic tumors compared with normal livers. Consistent with observations in the primary human CCA, flow cytometric analysis of hepatic tumors showed significantly elevated levels of CD45-positive leukocytes comprised of immunosuppressive G-MDSC compared with normal littermate controls (P = .0007). Also, a higher proportion of granulocytes in the bone marrow and blood were observed in spontaneous CCA mice compared with normal littermate controls.
These data suggest that the ELR+ chemokine/CXCR2 axes may potentially be involved in CCA pathogenesis and supports the utility of the spontaneous murine CCA model in preclinical evaluations of potential therapeutic interventions targeting this pathway.
Source: Ullman NA, et al. J Clin Oncol. 2020;38(4_suppl). Abstract 565.