Germline BRCA1 pathogenic variants and T cell dysfunction
- Author(s)
- Kay, J; Harris, MA; Lara Gonzalez, LE; van Geelen, CT; Clarke, KA; Virassamy, B; Caramia, F; Pang, JM; O'Malley, MMR; Hun, ML; Salgado, R; Thorne, H; Visvader, J; Neeson, PJ; Darcy, PK; Loi, S;
- Journal Title
- Immuno-oncology Technology
- Abstract
- BACKGROUND: Germline BRCA1 (gBRCA1) pathogenic variants (PVs) are the most common cause of inherited breast cancer. Preclinical studies have shown that homozygous loss of BRCA1 in T cells impairs T cell-mediated antitumour immunity. However, the consequences of heterozygous gBRCA1 on human T cell function are unknown. PATIENTS AND METHODS: We collected peripheral blood mononuclear cells (PBMCs) from healthy donors and treatment-naïve patients diagnosed with early-stage breast cancer with or without a gBRCA1 PV. T cells derived from PBMC were activated in vitro and analysed for phenotypic and functional differences. To investigate the impact of gBRCA1 PV on tumour-infiltrating lymphocytes (TILs), we carried out T cell receptor (TCR) sequencing and whole exome sequencing on triple negative breast cancer (TNBC) tumours from gBRCA1 carriers and wild-type (WT) patients. RESULTS: Patients with gBRCA1 PV had significantly reduced circulating T cell counts compared with WT individuals. BRCA1 protein was highly expressed in healthy donor activated T cells, but significantly reduced expression was observed in gBRCA1 patients compared with WT. Activated T cells from gBRCA1 carriers displayed a distinct transcriptional profile with significantly impaired proliferation and decreased effector molecule production. TCR sequencing of TILs extracted from TNBC tumours from gBRCA1 carriers revealed significantly more hyperexpanded T cell clones than in WT patients, with hyperexpansion correlating with increased tumour mutation burden (R (2) = 0.86), particularly frameshift mutations (R (2) = 0.72). CONCLUSIONS: Circulating T cells from gBRCA1 carriers exhibit intrinsic T cell dysfunction. This phenotype may be clinically relevant in the context of antitumour immunity, cancer development, progression and response to immunotherapy treatment.
- Publisher
- Elsevier
- Keywords
- Brca1; T cell dysfunction; T cell receptor; breast cancer; immunity; tumour-infiltrating lymphocyte
- Research Division(s)
- Cancer Biology and Stem Cells
- PubMed ID
- 42597706
- Publisher's Version
- https://doi.org/10.1016/j.iotech.2026.101601
- Open Access at Publisher's Site
https://doi.org/10.1016/j.iotech.2026.101601- Terms of Use/Rights Notice
- Refer to copyright notice on published article.
Creation Date: 2026-08-28 10:52:06
Last Modified: 2026-08-28 10:56:27