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

Frontiers in Immunology

Immunology

Samuele Massarut¹  Riccardo Dolcetti²  Valli De Re³  Elena Muraro³  Agostino Steffan³  Mariangela De Zorzi³  Simona Scalone⁴  Davide Lombardi⁴  Gianmaria Miolo⁴  Simon Spazzapan⁴  Tiziana Perin⁵ 

[1] Breast Surgery Unit, Centro di Riferimento Oncologico di Aviano (CRO Aviano), IRCCS, National Cancer Institute, Aviano, Italy;Centre for Cancer Immunotherapy, Peter MacCallum Cancer Centre, Melbourne, VIC, Australia;Sir Peter MacCallum Department of Oncology, The University of Melbourne, VIC, Australia;Department of Microbiology and Immunology, The University of Melbourne, VIC, Australia;Faculty of Medicine, The University of Queensland Diamantina Institute, Brisbane, QLD, Australia;Immunopathology and Cancer Biomarkers Units, Department of Translational Research, Centro di Riferimento Oncologico di Aviano (CRO), Istituto di Ricovero e Cura a Carattere Scientifico (IRCCS), Aviano, Italy;Medical Oncology and Cancer Prevention Unit, Centro di Riferimento Oncologico di Aviano (CRO), IRCCS, Aviano, Italy;Pathology Unit, Centro di Riferimento Oncologico di Aviano (CRO Aviano), IRCCS, National Cancer Institute, Aviano, Italy;

关键词: KIR;    HLA;    breast cancer;    trastuzumab;    ADCC;   

DOI  :  10.3389/fimmu.2021.791958

 received in 2021-10-09, accepted in 2021-12-20,  发布年份 2022

来源: Frontiers

【 摘 要 】

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.

【 授权许可】

Unknown   
Copyright © 2022 Muraro, De Zorzi, Miolo, Lombardi, Scalone, Spazzapan, Massarut, Perin, Dolcetti, Steffan and De Re