Germline BRCA1 pathogenic variants and T cell dysfunction.

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.