Title: Macrophage repolarisation in murine pancreatic cancer.
Funder: The Academy of Medical Sciences

Abstract: Novel therapeutic strategies are desperately required to overcome the dismal prognosis facing patients with pancreatic cancer (PDAC). The tumour microenvironment in PDAC is hostile, with a dense stromal reaction and abundant immune cells. Tumour associated macrophages (TAMs) comprise a significant proportion of the stroma. TAMs may be anti or pro tumourigenic (M1 or M2). In PDAC, the majority of TAMs are M2. They are highly immunosuppressive and limit immunogenic tumour cell death. In addition, PDAC is immunologically silent, which may be in part due to a paucity of tumour antigens and insufficient immune priming. Radiotherapy may overcome this by stimulating MHC I expression, increasing the intracellular peptide pool and generating neoantigens. In murine PDAC, radiotherapy is associated with a significant increase in M2 TAMs, thwarting any immunological benefits. We have previously shown that depletion of these TAMs permits the migration of CD8 T cells into the stroma, but leads to only a modest delay in tumour growth. We propose to repolarise TAMs towards an M1 anti-tumour phenotype, thereby harnessing this population which stimulates immunity and exerts anti-tumour effects. The gamma isoform of the lipid kinase PI3k (PI3k-gamma) is uniquely expressed in macrophages and is responsible for polarisation of TAMs towards an M2 phenotype. We aim to investigate whether PI3k-gamma reverses TAM polarisation in irradiated orthotopic PDAC tumours. We will analyse tumour growth kinetics, the immune infiltrate and the expression of immune checkpoint molecules on tumour infiltrating lymphocytes.

Lay abstract: Survival rates following a diagnosis of pancreatic cancer have not improved significantly for several decades. The prognosis remains extremely poor, with less than 1 in 20 people surviving for 5 years. One of the main challenges facing cancer scientists trying to develop new treatments is the microscopic structure of pancreatic tumours. In addition to tumour cells, there is an abundance of other cells that severely restrict the effectiveness of conventional cancer treatments. Foremost amongst these are a type of white blood cell called macrophages. Depending on the type of tumour, macrophages can either promote or inhibit tumour growth. In pancreatic cancer, the majority of macrophages tend to be of the type that promote tumour growth. Radiotherapy is not very effective in pancreatic cancer and causes an increase in tumour promoting macrophages. We have previously shown that by reducing the number of these macrophages after radiotherapy, mice with pancreatic cancer survive for longer, but are not cured. A new class of drug called IPI-549 specifically targets macrophages and keeps them in a state that may help to suppress tumour growth. We propose to test whether this drug is able to repurpose the macrophages present after radiotherapy so that they help to boost anti-tumour effects. We will measure changes in immune cell populations in tumours. These results may help us to determine if this treatment combination is likely to render tumours sensitive to newer classes of drugs that target the immune system.

Research activity codes: 2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: CANCER AND NEOPLASMS