Abstract
Simple SummaryPreclinical studies suggest that interactions between granulocyte colony-stimulating factor (G-CSF) and hypoxia-induced carbonic anhydrase IX regulate the trafficking and function of immune cells in the tumour microenvironment. We investigated the clinical significance of this crosstalk by analyzing the protein expression of G-CSF and macrophage markers by immunohistochemistry on a well-characterized tissue microarray series of invasive breast cancers. We report that high expression of G-CSF on breast carcinoma cells is linked with significantly improved survival in an important group of breast cancers that do not respond to hormonal therapy. These tumours were infiltrated by immune cells expressing biomarkers that can be targeted with immune checkpoint inhibitor drugs. In contrast, carbonic anhydrase IX expression was associated with unfavourable outcomes.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-CSFhigh expression showed a significant positive association with ER negativity, HER2 positivity, presence of CD163+ M2 macrophages, and CAIX expression. In univariate analysis, G-CSFhigh 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-CSFhigh/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.
Highlights
Granulocyte colony-stimulating factor (G-CSF) is a member of the colony-stimulating factor superfamily and exerts its biological effects by binding to the G-CSF receptor (GCSFR)
The objectives of this study were to investigate the immunohistochemical expression of G-CSF in a large series of breast cancers powered for correlation with clinicopathological features, carbonic anhydrase IX (CAIX) expression, and immune checkpoint biomarkers; and to examine the prognostic significance of G-CSF in relation to CAIX and CD163+ M2 macrophages using breast cancer-specific survival as the primary endpoint, and overall survival and relapse-free survival as secondary endpoints
After adjusting for standard clinicopathological features, high expression of G-CSF was significantly associated with better prognosis (Supplementary Table S3)
Summary
Granulocyte colony-stimulating factor (G-CSF) is a member of the colony-stimulating factor superfamily and exerts its biological effects by binding to the G-CSF receptor (GCSFR). The archetypal G-CSF/G-CSFR signalling pathway is critical for proliferation and survival of myeloid precursors and their subsequent differentiation into neutrophils with augmentation of their effector functions [1]. Recognition of these biological functions led to the establishment of G-CSF as a prophylactic and therapeutic agent for chemotherapyinduced febrile neutropenia [2]. Considering the robust relationship between inflammation and cancer, the role of G-CSF- and G-CSF-mobilized immune cells has been investigated in preclinical models of several non-hematopoietic malignancies, including breast cancer [3,4] These studies have implicated aberrant G-CSF/G-CSFR signalling with altered hematopoiesis, leading to the recruitment of immunosuppressive cells in the tumour microenvironment that potentiate migration, invasion, angiogenesis and metastasis [5,6,7,8,9,10,11,12,13]. In line with preclinical data, clinical studies evaluating G-CSF expression on tumour cells have shown an association with aggressive clinicopathological features and poor prognosis in solid organ malignancies such as clear cell renal cell carcinomas and cervical cancers [14,15]
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