Characterization and ex vivo functional properties of NKG2C+ NK cells with adaptive features in breast tumors
6 affiliations
- 1Centro de Investigaciones Oncológicas-Fundación Cáncer (FUCA)
- 2Servicio de Cirugía Oncoginecológica y Mastología, Instituto Alexander Fleming (IAF)
- 3Unidad de Mastología, Hospital Municipal “Profesor Dr. Bernardo Houssay”
- 4Servicio de Anatomía Patológica, del Instituto Alexander Fleming (IAF)
- 5Servicio de Anatomía Patológica, Hospital Municipal “Dr. Bernardo Houssay”
- 6Laboratorio de Evolución, Instituto de Ecología, Genética y Evolución de Buenos Aires (IEGEBA), Facultad de Ciencias Exactas y Naturales - Universidad de Buenos Aires (FCEN-UBA)
Abstract
Introduction: Adaptive Natural Killer cells are a specialized NK-cell subset with enhanced antibody-dependent effector functions, making them attractive candidates for cancer immunotherapy. Although circulating adaptive NK cells have demonstrated potent antitumor activity, their presence and functional status within the breast tumor microenvironment (TME) remain largely unknown.
Methods: Here, we investigated the infiltration, phenotype, functional properties, and clinical relevance of NKG2C ⁺ NK cells with adaptive features (aNK) in treatment-naïve breast cancer. Using paired peripheral blood, tumor, and adjacent non-tumoral breast tissue samples, together with functional assays and transcriptomic analyses from The Cancer Genome Atlas (TCGA), we characterized tumor-infiltrating aNK cells and evaluated their association with clinical outcome.
Results: aNK cells are present within breast tumors while preserving their phenotype and enhanced effector functions. Tumor-infiltrating aNK cells retained robust antibody-dependent degranulation and IFN-γ production. Complementary studies using peripheral blood-derived aNK cells further demonstrated their superior capacity to promote dendritic cell maturation, supporting their immunoregulatory potential. Moreover, we analyzed an adaptive NK-associated transcriptional signature in TCGA breast cancer samples and found that higher signature scores were associated with a longer progression-free interval and an immune microenvironment enriched in specific CD8 ⁺ T-cell populations.
Discussion: These findings indicate that aNK cells are functionally resilient to the suppressive breast TME, maintaining some specialized functions and immunoregulatory properties after tumor infiltration. Their persistence and association with favorable clinical outcome provide a rationale for further investigating their potential role in antibody-based immunotherapy and as a possible target for therapeutic strategies in BC.
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BibTeX
@article{bordignon2026characterization,
title = {{Characterization and ex vivo functional properties of NKG2C+ NK cells with adaptive features in breast tumors}},
author = {María Belén Bordignon and Ayelén Ivana Pesce Viglietti and Luciana Sabatini and Natalia Elizabeth Nuñez and Mora Amat and Verónica Fabiano and Santiago Nelson Sánchez and Sebastián Aebi and Paola Gabriela Brunacci and Nicolas Flaibani and Azul Perazzolo and Marcelo Triveño Quiroz and Florencia Cappuccio and Darío Ricardo Martín and Carlos Martín Loza and Marianela Ruth Ramírez and Federico Coló and José Mordoh and Estrella Mariel Levy},
journal = {Frontiers in Immunology},
year = {2026},
month = oct,
doi = {10.3389/fimmu.2026.1995578},
url = {https://www.frontiersin.org/articles/10.3389/fimmu.2026.1995578/full},
note = {CC BY 4.0},
}
RIS
TY - JOUR
TI - Characterization and ex vivo functional properties of NKG2C+ NK cells with adaptive features in breast tumors
AU - María Belén Bordignon
AU - Ayelén Ivana Pesce Viglietti
AU - Luciana Sabatini
AU - Natalia Elizabeth Nuñez
AU - Mora Amat
AU - Verónica Fabiano
AU - Santiago Nelson Sánchez
AU - Sebastián Aebi
AU - Paola Gabriela Brunacci
AU - Nicolas Flaibani
AU - Azul Perazzolo
AU - Marcelo Triveño Quiroz
AU - Florencia Cappuccio
AU - Darío Ricardo Martín
AU - Carlos Martín Loza
AU - Marianela Ruth Ramírez
AU - Federico Coló
AU - José Mordoh
AU - Estrella Mariel Levy
PY - 2026
DA - 2026/10/27
JO - Frontiers in Immunology
DO - 10.3389/fimmu.2026.1995578
UR - https://www.frontiersin.org/articles/10.3389/fimmu.2026.1995578/full
AB - Introduction: Adaptive Natural Killer cells are a specialized NK-cell subset with enhanced antibody-dependent effector functions, making them attractive candidates for cancer immunotherapy. Although circulating adaptive NK cells have demonstrated potent antitumor activity, their presence and functional status within the breast tumor microenvironment (TME) remain largely unknown. Methods: Here, we investigated the infiltration, phenotype, functional properties, and clinical relevance of NKG2C ⁺ NK cells with adaptive features (aNK) in treatment-naïve breast cancer. Using paired peripheral blood, tumor, and adjacent non-tumoral breast tissue samples, together with functional assays and transcriptomic analyses from The Cancer Genome Atlas (TCGA), we characterized tumor-infiltrating aNK cells and evaluated their association with clinical outcome. Results: aNK cells are present within breast tumors while preserving their phenotype and enhanced effector functions. Tumor-infiltrating aNK cells retained robust antibody-dependent degranulation and IFN-γ production. Complementary studies using peripheral blood-derived aNK cells further demonstrated their superior capacity to promote dendritic cell maturation, supporting their immunoregulatory potential. Moreover, we analyzed an adaptive NK-associated transcriptional signature in TCGA breast cancer samples and found that higher signature scores were associated with a longer progression-free interval and an immune microenvironment enriched in specific CD8 ⁺ T-cell populations. Discussion: These findings indicate that aNK cells are functionally resilient to the suppressive breast TME, maintaining some specialized functions and immunoregulatory properties after tumor infiltration. Their persistence and association with favorable clinical outcome provide a rationale for further investigating their potential role in antibody-based immunotherapy and as a possible target for therapeutic strategies in BC.
SN - 1664-3224
ER -