Poster Presentation 36th Lorne Cancer Conference 2024

Understanding changes in the immune microenvironment during the development of p53-deficient breast tumours with or without Brca1 loss (#131)

Xiaoyu Song 1 2 , Caleb Dawson 2 3 , Rosa Pascual 1 2 , Felicity Jackling 1 , Geoffrey Lindeman 1 4 5 , Jane Visvader 1 2
  1. ACRF Cancer Biology and Stem Cells Division, Walter and Eliza Hall Institute of Medical Research, Parkville, VIC, Australia
  2. Department of Medical Biology, The University of Melbourne, Parkville, VIC, Australia
  3. Immunology Division, Walter and Eliza Hall Institute of Medical Research, Parkville, VIC, Australia
  4. Department of Medicine, Royal Melbourne Hospital, The University of Melbourne, Parkville, VIC, Australia
  5. Parkville Familial Cancer Centre and Department of Medical Oncology, The Royal Melbourne Hospital and Peter MacCallum Cancer Centre, Parkville, VIC, Australia

Germline BRCA1-mutation carriers have higher susceptibility to breast cancer (BC), with a cumulative lifetime risk of 72% accompanied by aggressive pathological phenotypes. Most BRCA1-mutated breast tumours harbour aberrations in TP53 gene, which is one of the most frequently mutated genes in BC. TP53 mutation frequency is variable across BC subgroups, where TNBC has the highest prevalence (~80%). Women with TP53 pathogenic variants are predisposed to >100-fold risk of early-onset BC. BRCA1-deficient cells are vulnerable to DNA damage and chromosomal instability, potentially leading to a higher neoantigen load. p53 protein has fundamental roles in cancer immunity, indicating that tumorigenic mechanisms of TP53 mutation include immune modulation. To harness the key immune components in BRCA1/TP53-mutated BC and improve immunotherapy response, changes in the immune microenvironment (IM) during tumour development needs to be further understood. 

In this project, the IM compositions of two BC mouse models were extensively profiled: a Brca1/p53-deficient model and a p53-deficient mouse model. Using a 21-colour myeloid panel and a 25-colour lymphoid panel, both tumours and tumour adjacent mammary glands (hyperplastic stage) were depicted in comparison to the age-matched control mammary glands by spectral flow cytometry. In both models, only a few subtle changes occur at the hyperplastic stage, while the local immune environment is profoundly altered at the tumour stage. Both p53- and Brca1/p53- tumours show dramatic myeloid expansion accompanied by shrinkage of the lymphoid compartment. Neutrophils and macrophages become the dominant components in the IM of both genotype of tumours. Cycling CD8 T cells increased significantly in both models at the tumour stage. Notably, the two tumour models displayed profound heterogeneity in the myeloid compartment. with shared myeloid-dominant and strongly immuno-suppressive features. The finding that the two models manifest specific immune repertoires suggests that the underlying immune-modulating mechanisms are unique to genotype. The identified tumour-specific immune populations could serve as promising targets in future immunotherapeutic strategies for BRCA1/TP53-mutated BC. The spectral flow cytometry panels established here are also valuable tools for solid epithelial tumour-associated immunology studies.