Grant: Project Grant

Colorectal cancer (CRC) is the fourth cause of cancer death, and breast cancer is the leading cause of cancer death in women, worldwide. The tumour microenvironment consists of tumour cells and immune cells, and it has become clear that immune cells must be functional for long-term control of tumour development. However tumours secrete factors that inhibit immune cells, and promote the accumulation of dysfunctional immune cells termed immunosuppressive myeloid cells, which support tumour growth and spread. To address this, new immune checkpoint blockade (ICB) immunotherapies have been developed. However, for most cancer types ICB responses are limited, with the presence of immunosuppressive myeloid cells being a key barrier to success. The vast heterogeneity of immunosuppressive myeloid cells renders their identification and classification, and identification of the tumour-associated factors controlling their development, challenging. We have identified a cytokine - granulocyte colony stimulating factor (GCSF) - as a key factor driving the development of immunosuppressive cells, and found that inhibition of GCSF normalizes myeloid lineage composition, reduces tumour growth, and improves immunotherapy. Importantly we have also identified a novel myeloid subset present in both mice and humans, which develops in cancer. We have termed these cells "patrolling tumour enriched monocytes" (pTEMs). Our research plan is to comprehensively characterize tumour-induced alterations in myeloid subsets, and identify GCSF-gene regulatory networks underlying immunosuppressive myeloid cell developmental patterns. To do this, we will utilize mouse models of CRC and breast cancer. We will determine the spatial locations of immune cells within tumours. In addition, we will remove pTEMs from tumour bearing mice, and further characterize them with respect to their ability to regulate CD8+ T cells and NK cells (types of immune cells that kill tumours), to determine their role cancer.