IL-2- or IL-15-activated NK cells enhance Cetuximab-mediated activity against triple-negative breast cancer in xenografts and in breast cancer patients.
Triple-negative breast cancer (TNBC) patients do not benefit from target-specific treatments and is associated with a high relapse rate. Epidermal growth factor receptor is frequently expressed in TNBC and is a candidate for new therapies. In this work, we studied Cetuximab-mediated immune activity by NK cells. Thirteen activating/inhibitory receptors were examined on peripheral blood and tumor infiltrating NK cells. NK-cell functionality was evaluated using as effectors tumor-modulated NK cells and NK cells from patients. We evaluated the treatment with Cetuximab plus IL-2 or IL-15 in vivo in TNBC xenografts. Tumor NK-cells receptor profile showed upregulation of inhibitory receptors and downregulation of activating ones. Tumor-modulated NK cells were less cytotoxic. They could perform antibody-dependent cellular cytotoxicity (ADCC) triggered by Cetuximab, although impaired, it could still be restored by stimulation with IL-2 or IL-15. Patients with advanced disease displayed diminished levels of ADCC compared to healthy volunteers. ADCC was restored and potentiated with both cytokines, which were also effective in enhancing the therapeutic activity of Cetuximab in vivo. The combination of Cetuximab with IL-15 and IL-2 may be considered an attractive therapeutic approach to enhance the clinical efficacy of Cetuximab in TNBC.
Centro de Investigaciones Oncológicas - Fundación Cáncer FUCA, Buenos Aires, Argentina.
María P
MP
Roberti
Yamila S
YS
Rocca
Mora
M
Amat
María B
MB
Pampena
José
J
Loza
Federico
F
Coló
Verónica
V
Fabiano
Carlos M
CM
Loza
Juan M
JM
Arriaga
Michele
M
Bianchini
María M
MM
Barrio
Alicia I
AI
Bravo
Enzo
E
Domenichini
Reinaldo
R
Chacón
José
J
Mordoh
Estrella M
EM
Levy
D000328:Adult; D000818:Animals; D061067:Antibodies, Monoclonal, Humanized / Q000494:pharmacology*; D000920:Antibody-Dependent Cell Cytotoxicity / Q000187:drug effects / Q000276:immunology; D000970:Antineoplastic Agents / Q000494:pharmacology*; D001943:Breast Neoplasms / Q000188:drug therapy* / Q000276:immunology* / Q000473:pathology; D045744:Cell Line, Tumor; D000068818:Cetuximab; D005260:Female; D006801:Humans; D019409:Interleukin-15 / Q000494:pharmacology*; D007376:Interleukin-2 / Q000494:pharmacology*; D007694:Killer Cells, Natural / Q000187:drug effects* / Q000276:immunology*; D051379:Mice; D008819:Mice, Nude; D008875:Middle Aged; D023041:Xenograft Model Antitumor Assays
D061067:Antibodies, Monoclonal, Humanized; D000970:Antineoplastic Agents; D019409:Interleukin-15; D007376:Interleukin-2; D000068818:Cetuximab