Granulocyte Colony Stimulating Factor Expression in Breast Cancer and Its Association with Carbonic Anhydrase IX and Immune Checkpoints.

PURPOSE

Granulocyte colony-stimulating factor (G-CSF) and hypoxia modulate the tumour immune microenvironment. In model systems, hypoxia-induced carbonic anhydrase IX (CAIX) has been associated with G-CSF and immune responses, including M2 polarization of macrophages. We investigated whether these associations exist in human breast cancer specimens, their relation to breast cancer subtypes, and clinical outcome.

METHODS

Using validated protocols and prespecified scoring methodology, G-CSF expression on carcinoma cells and CD163 expression on tumour-associated macrophages were assayed by immunohistochemistry and applied to a tissue microarray series of 2960 primary excision specimens linked to clinicopathologic, biomarker, and outcome data.

RESULTS

G-CSF expression showed a significant positive association with ER negativity, HER2 positivity, presence of CD163+ M2 macrophages, and CAIX expression. In univariate analysis, G-CSF phenotype was associated with improved survival in non-luminal cases, although the CAIX+ subset had a significantly adverse prognosis. A significant positive association was observed between immune checkpoint biomarkers on tumour-infiltrating lymphocytes and both G-CSF- and CAIX-expressing carcinoma cells. Immune checkpoint biomarkers correlated significantly with favourable prognosis in G-CSF/non-luminal cases independent of standard clinicopathological features.

CONCLUSIONS

The prognostic associations linking G-CSF to immune biomarkers and CAIX strongly support their immunomodulatory roles in the tumour microenvironment.