Association of BRCA1- and BRCA2-deficiency with mutation burden, expression of PD-L1/PD-1, immune infiltrates, and T cell-inflamed signature in breast cancer - PubMed (original) (raw)
Association of BRCA1- and BRCA2-deficiency with mutation burden, expression of PD-L1/PD-1, immune infiltrates, and T cell-inflamed signature in breast cancer
Wei Xiong Wen et al. PLoS One. 2019.
Abstract
Immune checkpoint inhibitors have demonstrated effective anti-tumour response in cancer types with high mutation burden (e.g. melanoma) and in subset of cancers with features of genomic instability (e.g. mismatch-repair deficiency). One possible explanation for this effect is the increased expression of immune checkpoint molecules and pre-existing adaptive immune response in these cancers. Given that BRCA1 and BRCA2 are integral in maintaining genomic integrity, we hypothesise that the inactivation of these genes may give rise to breast cancers with such immunogenic phenotype. Therefore, using two large series of publicly available breast cancer datasets, namely that from The Cancer Genome Atlas and Wellcome Trust Institute, we sought to investigate the association between BRCA1- and BRCA2-deficiency with features of genomic instability, expression of PD-L1 and PD-1, landscape of inferred tumour-infiltrating immune cells, and T-cell inflamed signature in breast cancers. Here, we report that BRCA1 and BRCA2-deficient breast cancers were associated with features of genomic instability including increased mutation burden. Interestingly, BRCA1-, but not BRCA2-, deficient breast cancers were associated with increased expression of PD-L1 and PD-1, higher abundance of tumour-infiltrating immune cells, and enrichment of T cell-inflamed signature. The differences in immunophenotype between BRCA1- and BRCA2-deficient breast cancers can be attributed, in part, to PTEN gene mutation. Therefore, features of genomic instability such as that mediated by BRCA1- and BRCA2- deficiency in breast cancer were necessary, but not always sufficient, for yielding T cell-inflamed tumour microenvironment, and by extension, predicting clinical benefit from immunotherapy.
Conflict of interest statement
The authors have declared that no competing interests exist.
Figures
Fig 1. Proportion of mutational signature 3 and overall mutation burden by BRCA status in WSI and TCGA breast cancers.
** P < 0.01.
Fig 2
Volcano plots of immunostimulator (A-D) and immunoinhibitor (E-H) molecules in BRCA1- and BRCA2-deficient vs. BRCA-proficient breast cancers from WSI and TCGA. FC: fold change. KIR2DL3 with log2FC 14.5 in BRCA1-deficient vs. BRCA-proficient breast cancers from WSI shown at the boundary of the plot.
Fig 3
Relative enrichment of immune infiltrates in BRCA1- (A-B) and BRCA2-deficient (C-D) breast cancers compared to BRCA-proficient breast cancers from WSI and TCGA. ACT_B_cell: Activated B cell, ACT_CD4: Activated CD4 T cell, ACT_CD8: Activated CD8 T cell, ADC: Activated dendritic cell, CD56_BRIGHT: CD56bright natural killer cell, CD56_DIM: CD56dim natural killer cell, EOS: Eosinophil, IMM_B_CELL: Immature B cell, IMM_DC: Immature dendritic cell, MAC: Macrophage, MAST: Mast cell, MDSC: Myeloid-derived suppressor cell, MEM_B_CELL: Memory B cell, MON: Monocyte, NEU: Neutrophil, NK: Natural killer cell; NES: Normalized enrichment score, NKT: Natural killer T cell, PDC: Plasmacytoid dendritic cell, TCM_CD4: Central memory CD4 T cell, TCM_CD8: Central memory CD8 T cell, TEM_CD4: Effector memory CD4 T cell, TEM_CD8: Effector memory CD8 T cell, TFH: T follicular helper cell, TGD: γδ T cell, TH1: Type 1 T helper cell, TH17: Type 17 helper cell, TH2: Type 2 T helper cell, TREG: Regulatory T cell.
Fig 4. Association between BRCA status and T cell-inflamed signature in relation to PTEN mutation status.
(A) PTEN protein expression stratified by PTEN copy number alteration and point mutation. (B) Proportion of PTEN mutant samples stratified by BRCA status. (C-E) tSNE visualisation of BRCA1- and BRCA2-deficient breast cancers. Colour represents T cell-inflamed signature score divided at the median, PTEN mutation status, and BRCA status, respectively. (F-G) Distribution of T cell-inflamed signature scores in BRCA-proficient and BRCA1-deficient breast cancers with and without PTEN mutation. n.s.: Not statistically significant, ** P < 0.01.
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This project is funded by the International Medical University research grant IMU R056/2010 and Malaysian Ministry of Education grant FRGS/1/2016/SKK08/IMU/01/1. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.
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