Project ID CM-HD2023_44

ThemeCM-HD

Co Supervisor 1A School of Cancer and Pharmaceutical SciencesWebsite

Co Supervisor 1B School of Cancer and Pharmaceutical SciencesWebsite

Understanding lymph node determinants of therapy response

The lymphatic network and lymph nodes act as sentinels of the immune system. Lymphatic vessels continually deliver tissue-derived signals for lymph node constituents to assess and initiate an immune response when needed. This system, however may be hijacked by tumours as a route of escape.

Tumour-associated lymphatic vessels drain material away from tumours to connected lymph nodes. The fluid, or lymph, they carry is rich in tumour-derived proteins, metabolites, DNA and immune cells. These factors induce significant lymph node remodelling, driving changes to immune composition and organisation. This ultimately disrupts anti-tumour immunity and provides a friendly niche for disseminating tumour cells.

With our growing understanding of the intimate relationship between tumours and draining lymph nodes as cancers develop, we are now keen to understand how therapy impacts this relationship, and lymph node function. Therapeutic interventions perturb the tumour ecosystem, thus the signals and cells transported to lymph nodes will also change. We aim to identify the changes that occur in lymph nodes in response to treatment, if these are specific to responsive tumours, and if we can then use the knowledge gained to boost therapy effects in non-responders.

Objectives:
1. Deeply phenotype the tumour draining lymph node microenvironment and interactions within; combining spatial transcriptomics and imaging mass cytometry of therapy-treated murine and human tumours.
2. Mechanistically resolve the relationship between therapy response and lymph node adaptations in preclinical models, performing perturbation studies to identify interactions that may be disrupted to boost therapy response.

One representative publication from each co-supervisor:

• Davidson et al., Single cell RNA sequencing reveals a dynamic stromal niche within the evolving tumour microenvironment. Cell Reports. 1, 107628. (2020).

• Tumor-Infiltrating B Lymphocyte Profiling Identifies IgG-Biased, Clonally Expanded Prognostic Phenotypes in Triple-Negative Breast Cancer. Harris RJ et al. Cancer Res. Aug 15;81(16):4290-4304. (2021)