Enhancement of anti-tumour immunity by transduction with a Mycobacterium tuberculosis gene

Sfondrini, Lucia (2001). Enhancement of anti-tumour immunity by transduction with a Mycobacterium tuberculosis gene. PhD thesis The Open University.

DOI: https://doi.org/10.21954/ou.ro.0000f9b3

Abstract

As a strategy to enhance immune response against tumours by a "danger signal", the Mycobacterium tuberculosis Ag38 gene encoding an highly immunogenic protein has been transduced in tumour cells. The gene was stably expressed on tumour cell surface by using a retroviral vector modified to express the leader and transmembrane sequences of the Nerve Growth Factor Receptor. Transduced cells have been used as a cellular vaccine in syngeneic mice and their ability to elicit an anti-tumour response has been evaluated against both a transplanted tumour model and against a spontaneous tumour model.

In the transplanted melanoma model, vaccination with transduced cells induced a significant protection against subcutaneous or intravenous challenge with non transduced cells. In Ag38-transduced vaccinated mice a preferential Thl response was observed. Moreover, after challenge, a high titre of antibodies directed against tumour cells was detected in protected mice. Most of these antibodies were directed against endogenously expressed viral antigens, while no reactivity against melanocyte lineage specific antigens was observed.

In the HER2/Neu transgenic mice model, which spontaneously develop stochastic mammary tumours after a long latency period, the onset of tumour development was significantly delayed in mice vaccinated with Ag38-transduced cells. The delay in tumour development was increased when mice were vaccinated with the Ag38 transduced vaccine plus ·a systemic administration of IL-12 at . ~ low dose. Consistent with melanoma model, a preferential Thl profile was observed in mice in response to vaccination with Ag38-transduced cells and a CD3+CD8+ population able to respond to the tumour with IFN-y production was derived from these mice. No humoral response was induced in protected mice, while an activated CD4⁺ T cell population producing IL-4 was obtained from long-survived mice.