T-cell bispecific antibodies in node-positive breast cancer: novel therapeutic avenue for MHC class I loss variants.
Antibodies, Bispecific
/ administration & dosage
Antineoplastic Combined Chemotherapy Protocols
/ therapeutic use
Biomarkers, Tumor
/ metabolism
Breast Neoplasms
/ genetics
Female
Follow-Up Studies
Genetic Variation
Histocompatibility Antigens Class I
/ genetics
Humans
Lymph Nodes
/ immunology
Lymphatic Metastasis
Lymphocytes, Tumor-Infiltrating
/ immunology
Neoadjuvant Therapy
Neoplasm Invasiveness
Prognosis
Prospective Studies
Receptor, ErbB-2
/ metabolism
CEACAM5
HER2
HLA loss
T-cell bispecific antibodies (TCB)
breast cancer
tumor-infiltrating lymphocytes (TILs)
Journal
Annals of oncology : official journal of the European Society for Medical Oncology
ISSN: 1569-8041
Titre abrégé: Ann Oncol
Pays: England
ID NLM: 9007735
Informations de publication
Date de publication:
01 06 2019
01 06 2019
Historique:
pubmed:
30
3
2019
medline:
7
8
2020
entrez:
30
3
2019
Statut:
ppublish
Résumé
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. 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 CD3ε 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. 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 CD3ε and HER2 or CEACAM5 could bypass major histocompatibility complex (MHC) class I loss, partially rescuing T-cell functions in mLN. TCB should be developed in BC to circumvent low MHC/peptide complexes.
Sections du résumé
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 CD3ε 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 CD3ε 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.
Identifiants
pubmed: 30924846
pii: S0923-7534(19)31205-0
doi: 10.1093/annonc/mdz112
pmc: PMC7614969
mid: EMS185035
pii:
doi:
Substances chimiques
Antibodies, Bispecific
0
Biomarkers, Tumor
0
Histocompatibility Antigens Class I
0
ERBB2 protein, human
EC 2.7.10.1
Receptor, ErbB-2
EC 2.7.10.1
Types de publication
Journal Article
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
934-944Subventions
Organisme : Wellcome Trust
ID : 211179
Pays : United Kingdom
Organisme : Wellcome Trust
ID : 211179/Z/18/Z
Pays : United Kingdom
Commentaires et corrections
Type : CommentIn
Informations de copyright
© The Author(s) 2019. Published by Oxford University Press on behalf of the European Society for Medical Oncology. All rights reserved. For permissions, please email: journals.permissions@oup.com.
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