Role of macrophages in cancer immunotherapy: from patient multi-omic profiles to biological function

Despite the paradigm shift in cancer treatment triggered by immunotherapy, many patients fail to respond reflecting the dynamic interplay between cancer and the tumour microenvironment (TME). Monitoring this interplay is imperative to predict response to immunotherapy.

Recently, the Ciccarelli lab performed a multi-omic profile of immunotherapy-treated colorectal cancers showing that responsive tumours are characterised by deregulation of interferon-g pathways and rich infiltration of T cells and antigen-presenting tumour associated macrophages (TAMs), which engage in PD1/PDL1-mediated interactions1. The role of TAMs in the TME is unknown but they are likely to modulate anti-tumour immunity. Using spontaneous murine cancer models, the Arnold lab have identified interferon-regulated TAMs, which may be analogous to those in human cancer.

This translational and inter-disciplinary project will further characterise the role of this interferon regulated/CD74+ TAM subset(s) in the tumour microenvironment of murine and human tumours and their role in the response to immunotherapy.

This project will dissect the role of CD74+ TAMs and their role in the anti-tumour immune response through the following overarching project aims:

1) Employ spatial transcriptomics and imaging mass cytometry of immunotherapy-treated human gastrointestinal cancers and murine tumours to deeply phenotype (CD74+ /interferon-regulated TAMs and characterise their interactions with T cells in tissues sections.

2) Analyse transcriptomic datasets and employ computational approaches alongside in vivo models and in vitro culture techniques to identify candidate mediators of CD74+ TAM polarisation and recruitment at the tumour site, with a primary focus on studying the role of IFN-gamma as a key candidate polarisation molecule.

3) Mechanistically resolve the relationship between TAMs and their modulation of T cell responses via gene knockout and therapeutic intervention in murine models of...