The heme oxygenase-1 expressing perivascular macrophage subset as a non-redundant facilitator of cancer progression

Background: Tumour associated macrophages (TAMs) are a heterogeneous collection of cell phenotypes, with specialised effector functions that are dictated by the microenvironment in which they reside.

The prevalence of TAMs is a poor prognostic factor in a variety of cancers, but the key functional TAM phenotypes which contribute to cancer progression are still being resolved.

There is growing evidence that macrophages which reside in close proximity to blood vessels, termed perivascular macrophages, play a fundamental role in vasculature function.

We hypothesise that a perivascular TAM subset which expresses heme oxygenase-1 (HO-1), an enzyme which degrades haem to generate the biologically active by-products; biliverdin, ferrous iron and carbon monoxide represents a non-redundant facilitator of metastasis and immune suppression in the tumour microenvironment.

Aims: We will investigate perivascular HO-1+ TAMs, their biology, development and cellular interactions to elucidate their role in cancer progression.

We will compare and contrast these cells to those in healthy tissues and cutaneous wound healing, an inflammatory site which recruits HO-1+ macrophages and shares a stromal reaction similar to cancer, to further our understanding of the role of these cells and establish how to most effectively modulate the population therapeutically.

The relevance of these observations will be studied in human cancer. Methods: We will utilise the spontaneous MMTV-PyMT murine model of breast cancer for this study. We will use RNA sequencing, flow cytometry and imaging mass cytometry to investigate the HO-1+ TAM population.

Using in vivo models alongside an in vitro endothelial monolayer trans-well assay we will investigate the mechanism of action of perivascular HO-1+ TAMs.

We will use a novel HO-1 reporter mouse that we have generated to permit the ex vivo isolation of HO-1+ TAMs for transcriptomic analyses and in vivo use of intravital microscopy to study the development and dynamics of this population proximal to vasculature.

How the results of this research will be used: We will use these data to propel our knowledge of the basic biology of the perivascular HO-1+ TAM subset and their mechanistic role in metastasis and immune suppression.

We have a clinically relevant small molecule inhibitor of HO-1, tin mesoporphyrin (SnMP), which my laboratory is working towards taking into a first-in-human phase 1 trial for patients with cancer.

The insight gained for the role of HO-1 in the perivascular TAM subset will further support my lab’s work to translate HO-1 as a therapeutic target for the treatment of cancer.