Tumor-derived GCSF Alters Tumor and Systemic Immune System Cell Subset Composition and Signaling

Abstract

While immunotherapies such as immune checkpoint blockade and adoptive T cell therapy improve survival for a subset of human malignancies, many patients fail to respond. Phagocytes including dendritic cells (DCs), monocytes (Mos), and macrophages (MFs) orchestrate innate and adaptive immune responses against tumors. However, tumor-derived factors may limit immunotherapy effectiveness by altering phagocyte signal transduction, development, and activity. Using Cytometry by Time-of-Flight (CyTOF) we found that tumor-derived granulocyte-colony stimulating factor (G-CSF) altered myeloid cell distribution both locally and systemically. We distinguished a large number of G-CSF-induced immune cell subset and signal transduction pathway perturbations in tumor-bearing mice, including a prominent increase in immature neutrophil/myeloid-derived suppressor cell (Neut/MDSC) subsets and tumor-resident PD-L1+ Neut/MDSCs. G-CSF expression was also linked to distinct tumor-associated MF populations, decreased classic DCs, and splenomegaly characterized by increased splenic progenitors with diminished DC differentiation potential. G-CSF-dependent dysregulation of DC development was recapitulated in bone marrow (BM) cultures in vitro, using medium derived from G-CSF-expressing tumor cell cultures. Importantly, tumor-derived G-CSF impaired T cell adoptive cell therapy effectiveness and was associated with increased tumor volume and diminished survival of mice with mammary cancer. Treatment with neutralizing anti-G-CSF antibodies reduced colonic and circulatory Neut/MDSCs, normalized colonic immune cell composition and diminished tumor burden in a spontaneous model of mouse colon cancer. Analysis of human colorectal cancer (CRC) patient gene expression data revealed a significant correlation between survival and low G-CSF and Neut/MDSC gene expression. Our data suggest that normalizing G-CSF bioactivity may improve immunotherapy in cancers associated with G-CSF overexpression.

Squamous cell carcinoma‐derived G‐CSF promotes tumor growth and metastasis in mice through neutrophil recruitment and tumor cell proliferation, associated with poor prognosis of the patients

“…Neutrophils to lymphocytes ratio has been suggested as a prognostic marker in many tumor patients, including ESCC (Kosumi et al, 2016; Templeton et al, 2014; Zhou et al, 2017). Neutrophils or MDSCs can functionally inactivate anti‐tumor immune cells, especially T cells, and induce immunosuppression (Coffelt et al, 2015; Gabrilovich & Nagaraj, 2009; Mantovani et al, 2011; Matos et al, 2023). It was observed that the expression level of iNOS was highly upregulated in the peripheral neutrophils from tumor‐bearing mice in a murine breast cancer model (Coffelt et al, 2015).…”