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KIR-HLA Functional Repertoire Influences Trastuzumab Efficiency in Patients With HER2-Positive Breast Cancer

Trastuzumab induced a high rate of pathological Complete Response (pCR) in patients affected by locally advanced HER2-positive Breast Cancer (HER2-BC), by exploiting immune-mediated mechanisms as Antibody-Dependent Cell Cytotoxicity (ADCC) involving Natural Killer (NK) cells. Host’s immune genetics...

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Autores principales: Muraro, Elena, De Zorzi, Mariangela, Miolo, Gianmaria, Lombardi, Davide, Scalone, Simona, Spazzapan, Simon, Massarut, Samuele, Perin, Tiziana, Dolcetti, Riccardo, Steffan, Agostino, De Re, Valli
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Frontiers Media S.A. 2022
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8790064/
https://www.ncbi.nlm.nih.gov/pubmed/35095867
http://dx.doi.org/10.3389/fimmu.2021.791958
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author Muraro, Elena
De Zorzi, Mariangela
Miolo, Gianmaria
Lombardi, Davide
Scalone, Simona
Spazzapan, Simon
Massarut, Samuele
Perin, Tiziana
Dolcetti, Riccardo
Steffan, Agostino
De Re, Valli
author_facet Muraro, Elena
De Zorzi, Mariangela
Miolo, Gianmaria
Lombardi, Davide
Scalone, Simona
Spazzapan, Simon
Massarut, Samuele
Perin, Tiziana
Dolcetti, Riccardo
Steffan, Agostino
De Re, Valli
author_sort Muraro, Elena
collection PubMed
description Trastuzumab induced a high rate of pathological Complete Response (pCR) in patients affected by locally advanced HER2-positive Breast Cancer (HER2-BC), by exploiting immune-mediated mechanisms as Antibody-Dependent Cell Cytotoxicity (ADCC) involving Natural Killer (NK) cells. Host’s immune genetics could influence the response to therapy, through the expression of variants that characterize NK receptors involved in ADCC effectiveness. Killer cell immunoglobin-like receptors (KIRs) modulate NK cell activity through their binding to class-I Human Leukocyte Antigens (HLA). The impact of the KIR/HLA repertoire in HER2-BC is under study. We characterized KIR genotypes of 36 patients with locally advanced HER2-BC treated with neoadjuvant chemotherapy including trastuzumab. We monitored pCR achievement before surgery and Disease-Free Survival (DFS) and Overall Survival (OS) after adjuvant therapy. HLA, and Fc gamma receptor IIIa (FcγR3A) and IIa (FcγR2A) were genotyped through targeted PCR and Sanger sequencing in 35/36 patients. The KIR-HLA combinations were then described as functional haplotypes and divided in two main categories as inhibitory tel A and stimulatory tel B. Trastuzumab-dependent ADCC activity was monitored with an in vitro assay using a HER2-BC model and patients’ NK cells.We observed a higher frequency of KIR activators in patients who achieved a pCR compared to partial responders. During the study of functional haplotypes, individuals carrying a tel B haplotype showed greater ADCC efficiency than tel A cases. In subjects with the tel A haplotype the presence of the favorite V allele in FcγR3A receptor improved their low ADCC levels. Regardless of the haplotypes detected, the presence of KIR3DL2/HLA-A03 or A11 was always associated with the FcγR3A V allele, and therefore correlated with greater ADCC efficiency. However, this particular KIR receptor appeared to harm DFS and OS. Indeed, patients with tel B haplotype without KIR3DL2/HLA-A03 or A11 showed a better outcome. Our data, although preliminary, suggested a potential predictive role for KIR haplotype tel B, in identifying patients who achieve a pCR after neoadjuvant treatment with trastuzumab, and supported a negative prognostic impact of KIR3DL2/HLA-A03 or A11 in the adjuvant setting.
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spelling pubmed-87900642022-01-27 KIR-HLA Functional Repertoire Influences Trastuzumab Efficiency in Patients With HER2-Positive Breast Cancer Muraro, Elena De Zorzi, Mariangela Miolo, Gianmaria Lombardi, Davide Scalone, Simona Spazzapan, Simon Massarut, Samuele Perin, Tiziana Dolcetti, Riccardo Steffan, Agostino De Re, Valli Front Immunol Immunology Trastuzumab induced a high rate of pathological Complete Response (pCR) in patients affected by locally advanced HER2-positive Breast Cancer (HER2-BC), by exploiting immune-mediated mechanisms as Antibody-Dependent Cell Cytotoxicity (ADCC) involving Natural Killer (NK) cells. Host’s immune genetics could influence the response to therapy, through the expression of variants that characterize NK receptors involved in ADCC effectiveness. Killer cell immunoglobin-like receptors (KIRs) modulate NK cell activity through their binding to class-I Human Leukocyte Antigens (HLA). The impact of the KIR/HLA repertoire in HER2-BC is under study. We characterized KIR genotypes of 36 patients with locally advanced HER2-BC treated with neoadjuvant chemotherapy including trastuzumab. We monitored pCR achievement before surgery and Disease-Free Survival (DFS) and Overall Survival (OS) after adjuvant therapy. HLA, and Fc gamma receptor IIIa (FcγR3A) and IIa (FcγR2A) were genotyped through targeted PCR and Sanger sequencing in 35/36 patients. The KIR-HLA combinations were then described as functional haplotypes and divided in two main categories as inhibitory tel A and stimulatory tel B. Trastuzumab-dependent ADCC activity was monitored with an in vitro assay using a HER2-BC model and patients’ NK cells.We observed a higher frequency of KIR activators in patients who achieved a pCR compared to partial responders. During the study of functional haplotypes, individuals carrying a tel B haplotype showed greater ADCC efficiency than tel A cases. In subjects with the tel A haplotype the presence of the favorite V allele in FcγR3A receptor improved their low ADCC levels. Regardless of the haplotypes detected, the presence of KIR3DL2/HLA-A03 or A11 was always associated with the FcγR3A V allele, and therefore correlated with greater ADCC efficiency. However, this particular KIR receptor appeared to harm DFS and OS. Indeed, patients with tel B haplotype without KIR3DL2/HLA-A03 or A11 showed a better outcome. Our data, although preliminary, suggested a potential predictive role for KIR haplotype tel B, in identifying patients who achieve a pCR after neoadjuvant treatment with trastuzumab, and supported a negative prognostic impact of KIR3DL2/HLA-A03 or A11 in the adjuvant setting. Frontiers Media S.A. 2022-01-12 /pmc/articles/PMC8790064/ /pubmed/35095867 http://dx.doi.org/10.3389/fimmu.2021.791958 Text en Copyright © 2022 Muraro, De Zorzi, Miolo, Lombardi, Scalone, Spazzapan, Massarut, Perin, Dolcetti, Steffan and De Re https://creativecommons.org/licenses/by/4.0/This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.
spellingShingle Immunology
Muraro, Elena
De Zorzi, Mariangela
Miolo, Gianmaria
Lombardi, Davide
Scalone, Simona
Spazzapan, Simon
Massarut, Samuele
Perin, Tiziana
Dolcetti, Riccardo
Steffan, Agostino
De Re, Valli
KIR-HLA Functional Repertoire Influences Trastuzumab Efficiency in Patients With HER2-Positive Breast Cancer
title KIR-HLA Functional Repertoire Influences Trastuzumab Efficiency in Patients With HER2-Positive Breast Cancer
title_full KIR-HLA Functional Repertoire Influences Trastuzumab Efficiency in Patients With HER2-Positive Breast Cancer
title_fullStr KIR-HLA Functional Repertoire Influences Trastuzumab Efficiency in Patients With HER2-Positive Breast Cancer
title_full_unstemmed KIR-HLA Functional Repertoire Influences Trastuzumab Efficiency in Patients With HER2-Positive Breast Cancer
title_short KIR-HLA Functional Repertoire Influences Trastuzumab Efficiency in Patients With HER2-Positive Breast Cancer
title_sort kir-hla functional repertoire influences trastuzumab efficiency in patients with her2-positive breast cancer
topic Immunology
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8790064/
https://www.ncbi.nlm.nih.gov/pubmed/35095867
http://dx.doi.org/10.3389/fimmu.2021.791958
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