The overall short term objective is to characterize tumour infiltrating myeloid cell and their soluble mediators in a cohort of human tumour biopsies and experimental mouse models of human tumours and to analyze the molecular and cellular mechanisms underlying pro- versus anti-tumour programming of neoplastic tissues by the infiltrating myeloid cells compartment. This will be achieved by studying, the following aspects:
- Diversity and function of tumour associated macrophages (TAM).
- The role of mast cells in tumour development.
- The significance of myeloid cells and their mediators in chemotherapy responsiveness of cancer.
- The FcR and complement mediated activation of myeloid cells by tumour specific antibodies.
- The interplay between endothelial cells and myeloid cells in the tumour microenvironment.
- Immunomodulatory therapeutic antibodies targeting the tumour microenvironment and interacting with the myeloid cell compartment.
- Small molecules interfering with myeloid cell specific effector pathways. These studies will result in the identification of new potential targets for new diagnostic and therapeutic strategies by the industrial partners of the TIMCC network (long term objective).
Work Package 1. Human tumours: Biopsies
Genomic characterization, proteomics and bioinformatics on the myeloid cell compartment in human tumour biopsies
- 1.1 Genomic characterization of subsets of human tumour-associated macrophages (UBO-LIMES)
- 1.2 Archived samples from human (and murine) myeloid subsets (QMUL)
- 1.3 The interaction between myeloid cells in the tumour microenvironment and human prostate cancer and squamous cell carcinoma of the head and neck (SCCHN) (NKI)
Work Package 2. Mouse models: Experimental Tumours
The tumour infiltrating myeloid cell compartment in experimental mouse tumour models
- 2.1 The role of antibody and FcR/complement mediated pathways in tumour development (LUMC)
- 2.2 Identification and genomic characterization of TAM in a murine model of breast cancer (UBO-LIMES)
- 2.3 Macrophage polarization in light of kinase signaling pathways (QMUL)
- 2.4 The role of Mast cells in tumour development (TUD)
- 2.5 Impact of mast cells on the composition of the hematopoietic cell population infiltrating the stroma of epidermal tumours (TUD)
Work Package 3. Therapy: Antibodies / small molecules / chemotherapy
The tumour infiltrating myeloid cell compartment in therapy
- 3.1 The FcR/complement mediated activation of therapeutic myeloid effector pathways (LUMC)
- 3.2 The effect of CD40 stimulating therapy on endothelial activation and recruitment of myeloid cells in tumours (UU)
- 3.3 The effect of vasculature targeted antibody therapy on the immature myeloid cell population and the vascular phenotype in the tumour (UU)
- 3.4 The functional significance of myeloid cells and their mediators in chemotherapy responsiveness of cancer (NKI)
- 3.5 Development and analysis of antibodies targeting immunomodulatory receptors (Alligator)
- 3.6 Effect of small molecule myeloid modulators on tumour development (Synovo)