Final Report Summary - MACTHERVAC (Modulation of a novel population of immune suppressive tumoural macrophages and the therapeutic vaccination of cancer)
Unprecedented clinical outcomes have been achieved in a variety of cancers by targeting immune checkpoint receptors. However, a large proportion of patients still do not respond to the current therapies, suggesting that further important targets might still exist. This project set out to investigate heme oxygenase-1 (HO-1) for its role in tumour progression and as an immunotherapy target in cancer. HO-1 is an enzyme that is expressed in a wide variety of cancers and is responsible for the breakdown of haem to generate carbon monoxide, biliverdin and ferrous iron. Using preclinical models of cancer, we characterised the HO-1 expressing cells to be a subset of tumour associated macrophages (TAMs). The transcriptomic profiles of HO-1+ TAMs revealed that they had a ‘wound healing’ gene signature. We characterised the cytokine milieu of the tumour and healing wound microenvironments and identified interleukin-6 to be a potent driver of the HO-1+ TAM phenotype in vivo. To investigate the role of HO-1 in tumour progression, we utilised pharmacological inhibition of HO activity using tin mesoporphyrin (SnMP) alongside an in vivo model in which we had genetically inactivated the Hmox1 gene in the macrophages. Harnessing the immune-stimulating effects of cytotoxic chemotherapy, we demonstrated that inhibiting HO-1 activity in the tumour microenvironment efficiently alleviates immune suppression and permits the chemotherapy-elicited anti-tumour immune response to control tumour growth. Further to this, we demonstrated using our in vivo models of cancer that HO-1 activity facilitates pulmonary metastasis. Using an in vitro model of transendothelial migration, we demonstrated that HO-1 expressing macrophages facilitate HO-dependent transendothelial migration of tumour cells, a critical step in the metastatic cascade. In summary, this project has shed new light on HO-1 and its pivotal role in tumour progression.