Open Collections

Matos, Israel

University of British Columbia

Immunotherapy has improved patient survival in a subset of human malignancies. However, many patients do not respond to current therapies highlighting the need to better understand the interactions between tumours and the immune system. Phagocytes, such as dendritic cells (DCs), macrophages, and myeloid-derived suppressor cells (MDSCs), are critical in orchestrating or antagonizing innate and adaptive immune responses against tumours. In turn, phagocyte activity and development are dysregulated by tumour-derived factors. We previously identified granulocyte colony-stimulating factor (G-CSF) as a potent tumour-derived cytokine that alters phagocyte development and function. Using Cytometry by Time-of-Flight (CyTOF), we found that growth of G-CSF-expressing tumours led to a systemic accumulation of a complex mixture of myeloid cells and their progenitors, and perturbations in a wide variety of signalling pathways throughout the immune system. G-CSF significantly blocked the development of CD103⁺ classic dendritic cells (cDC1s), which are associated with improved cancer treatment outcomes and strong CD8⁺ cytotoxic T cell activity. Correspondingly, loss of tumour secreted-G-CSF improved adoptive T cell therapy of breast cancer tumours. In addition, treatment of colon cancer-bearing mice with neutralizing anti-G-CSF antibodies reduced MDSC accumulation, normalized colonic immune cell composition, and diminished tumour burden. Further, better patient survival was found to correlate with low G-CSF and neut/MDSC gene expression through analysis of patient CRC gene expression data. Altogether, our data suggest that G-CSF can induce myeloid lineage perturbations and immunosuppression and that modulating G-CSF bioactivity could improve immunotherapy efficacy in cancers associated with over-expression of G-CSF. Finally, we provide evidence that neutralization of human G-CSF delays tumour growth in humanized mouse models systems.

Text

2023-01-31

Attribution-NonCommercial-NoDerivatives 4.0 International

http://hdl.handle.net/2429/78847

Microbiology and Immunology

University of British Columbia

UBCV

http://creativecommons.org/licenses/by-nc-nd/4.0/