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Cancer Immunol Res. 2017 Apr;5(4):292-299. doi: 10.1158/2326-6066.CIR-16-0195. Epub 2017 Mar 2.

Clinical Impact of Tumor DNA Repair Expression and T-cell Infiltration in Breast Cancers.

Author information

1
Department of Pathology, Division of Cancer and Stem Cells, School of Medicine, University of Nottingham, Nottingham, United Kingdom.
2
Academic Unit of Oncology, Division of Cancer and Stem Cells, School of Medicine, University of Nottingham, Nottingham, United Kingdom.
3
Department of Oncology, Nottingham University Hospitals, Nottingham, United Kingdom.
4
Academic Unit of Oncology, Division of Cancer and Stem Cells, School of Medicine, University of Nottingham, Nottingham, United Kingdom. srinivasan.madhusudan@nottingham.ac.uk.

Abstract

Impaired DNA repair drives mutagenicity, which increases neoantigen load and immunogenicity. We investigated the expression of proteins involved in the DNA damage response (ATM, Chk2), double-strand break repair (BRCA1, BLM, WRN, RECQL4, RECQL5, TOPO2A, DNA-PKcs, Ku70/Ku80), nucleotide excision repair (ERCC1), base excision repair (XRCC1, pol β, FEN1, PARP1), and immune responses (CD8, PD-1, PD-L1, FOXP3) in 1,269 breast cancers and validated our findings in an independent estrogen receptor-negative (ER-) cohort (n = 279). Patients with tumors that expressed low XRCC1, low ATM, and low BRCA1 were not only associated with high numbers of CD8+ tumor-infiltrating lymphocytes, but were also linked to higher grades, high proliferation indexes, presence of dedifferentiated cells, ER- cells, and poor survival (all P ≤ 0.01). PD-1+ or PD-L1+ breast cancers with low XRCC1 were also linked to an aggressive phenotype that was high grade, had high proliferation indexes, contained dedifferentiated cells and ER- (all with P values ≤ 0.01), and poor survival (P = 0.00021 and P = 0.00022, for PD-1+ and PD-L1+ cancers, respectively) including in an independent ER- validation cohort (P = 0.007 and P = 0.047, respectively). We conclude that the interplay between DNA repair, CD8, PD-L1, and PD-1 can promote aggressive tumor phenotypes. XRCC1-directed personalization of immune checkpoint inhibitor therapy may be feasible and warrants further investigation in breast cancer. Cancer Immunol Res; 5(4); 292-9. ©2017 AACR.

PMID:
28254786
DOI:
10.1158/2326-6066.CIR-16-0195
[Indexed for MEDLINE]
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