Flash Talk and Poster Presentation 36th Lorne Cancer Conference 2024

Intrinsic Effects of Germline BRCA1 Mutations on Activated Peripheral Human T Cell Phenotypes (#102)

Jasmine Kay 1 2 , Balaji Virassamy 1 2 , Kylie A Clarke 2 , Franco Caramia 2 , Stefanie Stirl 2 , Michael A Harris 1 2 , Nuria Chic 2 , Valerie Setiono 2 , Michael L Hun 1 2 , Alexandra Smith 2 , Lody Mokdsi 2 , Genna Glavich 2 , Heather Thorne 2 , Phillip K Darcy 1 2 , Sherene Loi 1 2
  1. Peter MacCallum Department of Oncology, The University of Melbourne, Melbourne, Australia
  2. Peter MacCallum Cancer Centre, Reservoir, VIC, Australia

Inherited mutations in the breast cancer susceptibility genes BRCA1 and BRCA2 increase the chances of developing breast cancer by up to 70%, and largely present as aggressive triple negative breast cancer (TNBC) in young carriers. Immune checkpoint blockade (ICB) has shown encouraging results in TNBC, with particularly high responses reported in patients carrying BRCA2 mutations, but not BRCA1 mutations.

BRCA1 plays a key role in DNA repair and proliferation control. However, it is unknown how germline BRCA1 mutations impact immune function in carriers. BRCA1 mutation carriers have a lower age of cancer onset compared to non-carriers, reminiscent of poor tumour immunosurveillance. Moreover, recent murine studies have shown that BRCA1 may play a key role in T cell function.

The aim of this study was to investigate whether heterozygous mutations in BRCA1 impact the phenotype of human peripheral T cells, which may impede with cancer immunosurveillance and/or response to treatment. We hypothesised that as T cells proliferate rapidly upon activation, BRCA1 becomes involved in T cell cycle control, with protein-truncating mutations leading to altered cell phenotypes.

We show that BRCA1 mutation carriers have reduced levels of peripheral T cells compared to wild-type donors. Using gene expression analyses we established that BRCA1 is highly upregulated in activated human peripheral T cells, and heterozygous mutations can reduce its expression. Using bulk RNA sequencing, we observed an altered transcriptomic profile in stimulated peripheral T cells from BRCA1 carriers, which showed a highly active and proliferative CD4+ phenotype, compared to wildtype controls. This analysis also revealed an increase in immunosuppressive CD4+ cells in BRCA1 carriers, compared to wildtype. Flow cytometry analysis corroborated these results. T cell receptor (TCR) sequencing of tumour samples also revealed an impediment in the expansion of T cells within tumours of BRCA1 carriers, compared to wildtype controls. Though preliminary, these findings suggest that germline heterozygous BRCA1 mutations in human T cells have an intrinsic effect on their activation and phenotype in vitro, which may translate to reduced tumour-control in carrier patients. Overall, our findings lay the foundation for further research into the novel role of BRCA1 in human and anti-tumour immunity.

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