Oral Presentation Australian Epigenetics Alliance Conference 2022

Immune regulation of the premetastatic niche formation in triple-negative breast cancer (#27)

Laura Rodriguez de la Fuente 1 2 3 , Yolanda Colino Sanguino 2 4 , Jeron Venhuizen 1 , Andrew Law 1 3 , David Gallego Ortega 1 3 5 , Fatima Valdes Mora 2 4
  1. Tumour Development Laboratory, The Kinghorn Cancer Centre, Garvan Institute of Medical Research, Sydney, NSW, Australia
  2. Cancer Epigenetic Biology and Therapeutics, Children's Cancer Institute, Sydney, New South Wales, Australia
  3. St. Vincent's Clinical School, Faculty of Medicine, UNSW, Sydney, NSW, Australia
  4. School of Women's and Children's Health, Faculty of Medicine, UNSW, Sydney, NSW, Australia
  5. Centre for Single Cell Technology, School of Biomedical Engineering, Faculty of Engineering and IT, University of Technology Sydney, Sydeney, NSW, Australia

Introduction: The prognosis for patients with triple-negative breast cancer (TNBC) remains poor, with newly developed immunotherapies failing to produce the benefits seen in other cancers. This failure is often associated with the presence of myeloid-derived suppressor cells (MDSCs): an immune population with high plasticity and potent immunosuppressive capacity that plays an active role in the development of metastasis, the primary cause of death in TNBC patients. Targeting MDSCs is an attractive therapeutic strategy, however, the specific molecular features that define their identity, and the inflammatory mechanisms these cells employ to drive metastatic spread, remain elusive.

Materials and methods: Using a single-cell transcriptomic approach, we profiled the tumour microenvironment and lung cellular ecosystem before and after metastatic colonization in the highly metastatic 4T1.2 model of TNBC.  Comparatively, we used the non-metastatic 67NR model as a baseline to identify the pro-metastatic MDSCs and define the specific mechanisms that contribute to cancer dissemination.

Results and discussion: Our scRNAseq approach revealed the composition and functional diversity of inflammatory cells in tumours and metastatic sites, identifying 3 subclasses of granulocytic MDSCs involved in the formation of the pre-metastatic niche and metastasis. We further characterized these pro-metastatic MDSCs by looking at their immunosuppressive activity and activated pathways for their specific targeting without affecting other healthy myeloid populations. Targeting the epigenome of MDSCs to differentiate them into a non-malignant phenotype will restore their antitumor functions and reestablish the efficacy of the current immunotherapies.

Conclusion: This research provides a comprehensive spatial-temporal map of the pre-metastatic niche formation in TNBC. Our definition of pro-metastatic MDSCs is a step forward for designing new strategies to efficiently reprogram immunosuppressive mechanisms and stimulate antitumor immunity, ultimately paving the way for the development of the next generation of immunotherapy for metastatic breast cancer.