Journal
ANNALS OF ONCOLOGY
Volume 30, Issue 6, Pages 934-944Publisher
OXFORD UNIV PRESS
DOI: 10.1093/annonc/mdz112
Keywords
breast cancer; tumor-infiltrating lymphocytes (TILs); T-cell bispecific antibodies (TCB); HER2; CEACAM5; HLA loss
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Funding
- ROCHE
- Institut National du Cancer (INCa)
- ANR
- Ligue contre le cancer
- Swiss Bridge Foundation
- ISREC Foundation
- LABEX OncoImmunology
- la direction generale de l'offre de soins (DGOS)
- Universite ParisSud
- SIRIC SOCRATE [INCa/DGOS/INSERM 6043]
- PIA2 TORINO-LUMIERE
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Background Tumor-infiltrating lymphocytes (TILs) represent a prognostic factor for survival in primary breast cancer (BC). Nonetheless, neoepitope load and TILs cytolytic activity are modest in BC, compromising the efficacy of immune-activating antibodies, which do not yet compete against immunogenic chemotherapy. Patients and methods We analyzed by functional flow cytometry the immune dynamics of primary and metastatic axillary nodes [metastatic lymph nodes (mLN)] in early BC (EBC) after exposure to T-cell bispecific antibodies (TCB) bridging CD3 epsilon and human epidermal growth factor receptor 2 (HER2) or Carcinoembryonic Antigen-Related Cell Adhesion Molecule 5 (CEACAM5), before and after chemotherapy. Human leukocyte antigen (HLA) class I loss was assessed by whole exome sequencing and immunohistochemistry. One hundred primary BC, 64 surrounding healthy tissue' and 24 mLN-related parameters were analyzed. Results HLA loss of heterozygosity was observed in EBC, at a clonal and subclonal level and was associated with regulatory T cells and T-cell immunoglobulin and mucin-domain-3 expression restraining the immuno-stimulatory effects of neoadjuvant chemotherapy. TCB bridging CD3 epsilon and HER2 or CEACAM5 could bypass major histocompatibility complex (MHC) class I loss, partially rescuing T-cell functions in mLN. Conclusion TCB should be developed in BC to circumvent low MHC/peptide complexes.
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