Analysis of tumour infiltrating leukocytes in murine models of Cancer.

Abstract

This project provides a novel, and broad approach to induce anti-tumour responses against various tumour types without the need for personalised therapies and with minimal adverse effects. Intratumoural injection of complete Freund's adjuvant (CFA), an emulsion of heat-killed Mycobacterium butyricum, is a novel and effective cancer immunotherapy currently in clinical trial at the Canberra Hospital. This PhD project focused on correlating the efficacy of CFA immunotherapy and immune cell infiltration in murine tumours, utilising the novel method of fine-needle aspiration. CFA was found to be an effective anti-cancer treatment in murine tumour models for mastocytoma and breast cancer. By identifying the essential immune infiltrates for effective treatment, I aimed to improve the efficacy of intratumoural CFA by manipulating the anti-cancer immune response.

Increased toll-like receptor stimulation, through combination with 'Coley's toxins', was successful at inducing an improved anti-cancer response, increasing the efficacy of CFA treatment. It is generally assumed that T lymphocytes are key in the induction of anti-cancer responses, however, the results of this project propose a more important role of the innate immune system, specifically neutrophils, in the generation of an anti-cancer immune response. Increased neutrophil infiltration through CFA and Coley's toxin treatments correlated with increased survival in mastocytoma; however forced neutrophil chemotaxis using CXCL8 did not further improve survival. The combination of CFA with immune checkpoint inhibitor immunotherapies was also investigated and showed that the responses were highly dependent on tumour models; with additive benefit in a colorectal cancer model.