Skip to main content

Modulation of a novel population of immune suppressive tumoural macrophages and the therapeutic vaccination of cancer

Objective

The therapeutic vaccination against breast cancer, and more widely all solid tumours, has largely been ineffective in clinical trials. This failure has been attributed to ‘immune editing’ of the cancerous cells, or to suppression of T cell functions within the tumour. In relation to the later, we have identified a novel population of tumoural macrophages, marked by the expression of fibroblast activation protein-alpha (FAP) which can mediate tumoural immune suppression through the enzyme heme oxygenase-1 (HO-1). Selective inhibition of HO-1 with tin mesoporphyrin (SnMP), a drug which has already been administered to infants for the treatment of neonatal jaundice, permits immunological control of tumour growth in transplantable Lewis lung carcinoma tumours. This proposal seeks to evaluate SnMP as a novel cancer immunotherapy for the treatment of breast cancer. We have demonstrated that HO-1+ cells are recruited into mammary tumours of a relevant spontaneous murine model of breast cancer. A vaccine strategy will be developed targeting telomerase, a vaccine target already in clinical trial for human breast cancer. The effect on mammary tumour growth of a vaccine induced anti-tumour immune response, alongside HO-1 inhibition to alleviate immune suppression, will be assessed. Lung metastases in these mice, and their response to treatment, will also be studied. The HO-1 expressing cells in human breast cancer will be quantitated and characterised at both the protein and transcriptome levels to validate the approach. Novel immuno-therapies directed at modulating HO-1 expression will also be investigated, facilitated by the development of a transgenic HO-1 reporter mouse which will co-express green fluorescent protein and luciferase driven by the promoter and response elements of the HO-1 gene. As cancer vaccines have already been developed, and as we have identified a drug, SnMP, which may circumvent tumoural immune suppression, this proposal is clinically relevant.

Call for proposal

ERC-2013-StG
See other projects for this call

Funding Scheme

ERC-SG - ERC Starting Grant

Host institution

KING'S COLLEGE LONDON
Address
Strand
WC2R 2LS London
United Kingdom
Activity type
Higher or Secondary Education Establishments
EU contribution
€ 1 499 994
Principal investigator
James Noble Arnold (Dr.)
Administrative Contact
Paul Labbett (Mr.)

Beneficiaries (1)

KING'S COLLEGE LONDON
United Kingdom
EU contribution
€ 1 499 994
Address
Strand
WC2R 2LS London
Activity type
Higher or Secondary Education Establishments
Principal investigator
James Noble Arnold (Dr.)
Administrative Contact
Paul Labbett (Mr.)