The selective recruitment of regulatory t cells to human colorectal cancer

Ward, Stephen Thomas (2014). The selective recruitment of regulatory t cells to human colorectal cancer. University of Birmingham. Ph.D.

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Abstract

Regulatory T cells (Treg) are enriched in tumour tissue relative to other compartments. Anti-tumour immunity is promoted through their depletion. It is hypothesised that Treg are recruited to human colorectal cancer (CRC) via a specific combination of chemokine receptors and integrins, blockade of which reduces tumour Treg recruitment, ameliorating the anti-tumour immune response.
A systematic examination was conducted of receptors expressed by CRC-isolated Treg and the cognate ligands expressed by CRC. The effects of receptor inhibition were tested in murine models of colorectal cancer.
Human CRC-infiltrating Treg exhibit a specific chemokine receptor signature, expressing significantly higher levels of CCR5 than conventional T cells. CRC expresses the ligands for CCR5 at significantly higher levels than distal tissue. Isolated Treg migrated towards CCR5 ligands in vitro and suppressed allogeneic T cell proliferation. CCR5 inhibition in murine models of CRC led to delayed tumour growth but had no effect on tumour Treg infiltration compared with vehicle control.
CCR5 inhibition is unlikely to provide any significant reduction in the infiltration of Treg into human CRC. Given the effects CCR5 inhibition had on tumour growth, CCR5 antagonists command further investigation into their potential role as novel therapeutic agents in the treatment armoury against human CRC.

Type of Work:

Thesis (Doctorates > Ph.D.)

Award Type:

Doctorates > Ph.D.

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