Overexpression of CD85j in TNBC patients inhibits Cetuximab-mediated NK-cell ADCC but can be restored with CD85j functional blockade.
Clinical studies suggest that triple negative breast cancer (TNBC) patients with epidermal growth factor receptor (EGFR)-expressing tumors could benefit from therapy with Cetuximab, which targets EGFR. NK cells are the primary effectors of antibody (Ab)-dependent cell-mediated cytotoxicity (ADCC) and thus play a role in Ab-based therapies. We have previously described diminished levels of Cetuximab-mediated ADCC in vitro in patients with advanced breast cancer. Here, we investigated the potential causes of this NK-cell functional deficiency. We characterized NK-cell activating/inhibitory receptors in the peripheral blood of breast cancer patients and found CD85j inhibitory receptor overexpression. The capacity of NK cells to perform Cetuximab-triggered ADCC against TNBC cells correlated inversely with CD85j expression, even in the presence of the stimulatory cytokines IL-2 or IL-15. Hence, patients expressing high levels of CD85j had an impaired ability to lyse TNBC cells in the presence of Cetuximab. We also found that CD85j overexpression was associated with HLA-I and soluble HLA-G expression by tumors. A CD85j functional blockade with a CD85j antagonist Ab restored ADCC levels in breast cancer patients and reverted this negative effect. Our data suggest that strategies that overcome the hurdles of immune activation could improve Cetuximab clinical efficacy.
Centro de Investigaciones Oncológicas CIO-FUCA, Ciudad de Buenos Aires, Argentina.
María P
MP
Roberti
Centro de Investigaciones Oncológicas CIO-FUCA, Ciudad de Buenos Aires, Argentina.
Estefanía P
EP
Juliá
Fundación Instituto Leloir-IIBBA, Ciudad de Buenos Aires, Argentina.
Yamila S
YS
Rocca
Instituto Alexander Fleming, Ciudad de Buenos Aires, Argentina.
Mora
M
Amat
Hospital Eva Perón, San Martín, Provincia de Buenos Aires, Argentina.
Alicia I
AI
Bravo
Instituto Alexander Fleming, Ciudad de Buenos Aires, Argentina.
José
J
Loza
Instituto Alexander Fleming, Ciudad de Buenos Aires, Argentina.
Federico
F
Coló
Instituto Alexander Fleming, Ciudad de Buenos Aires, Argentina.
Carlos M
CM
Loza
Instituto Alexander Fleming, Ciudad de Buenos Aires, Argentina.
Verónica
V
Fabiano
Instituto Alexander Fleming, Ciudad de Buenos Aires, Argentina.
Mercedes
M
Maino
Hospital de Clínicas José de San Martín, Ciudad de Buenos Aires, Argentina.
Ariel
A
Podhorzer
Hospital de Clínicas José de San Martín, Ciudad de Buenos Aires, Argentina.
Leonardo
L
Fainboim
Centro de Investigaciones Oncológicas CIO-FUCA, Ciudad de Buenos Aires, Argentina.
María M
MM
Barrio
Centro de Investigaciones Oncológicas CIO-FUCA, Ciudad de Buenos Aires, Argentina.|Fundación Instituto Leloir-IIBBA, Ciudad de Buenos Aires, Argentina.|Instituto Alexander Fleming, Ciudad de Buenos Aires, Argentina.
José
J
Mordoh
Centro de Investigaciones Oncológicas CIO-FUCA, Ciudad de Buenos Aires, Argentina.
Estrella M
EM
Levy
D000328:Adult; D061067:Antibodies, Monoclonal, Humanized / Q000494:pharmacology*; D000920:Antibody-Dependent Cell Cytotoxicity; D015703:Antigens, CD / Q000378:metabolism*; D000970:Antineoplastic Agents / Q000494:pharmacology; D016022:Case-Control Studies; D000068818:Cetuximab; D066246:ErbB Receptors / Q000037:antagonists & inhibitors; D005260:Female; D006680:HLA Antigens / Q000378:metabolism; D059951:HLA-G Antigens / Q000378:metabolism; D006801:Humans; D020014:K562 Cells; D007694:Killer Cells, Natural / Q000276:immunology*; D000075362:Leukocyte Immunoglobulin-like Receptor B1; D008875:Middle Aged; D011971:Receptors, Immunologic / Q000037:antagonists & inhibitors* / Q000378:metabolism*; D064726:Triple Negative Breast Neoplasms / Q000276:immunology* / Q000628:therapy*; D055815:Young Adult
D061067:Antibodies, Monoclonal, Humanized; D015703:Antigens, CD; D000970:Antineoplastic Agents; D006680:HLA Antigens; D059951:HLA-G Antigens; C105299:LILRB1 protein, human; D000075362:Leukocyte Immunoglobulin-like Receptor B1; D011971:Receptors, Immunologic; C512478:EGFR protein, human; D066246:ErbB Receptors; D000068818:Cetuximab
ADCC; CD85j; Cetuximab; EGFR; NK cells; Triple negative breast cancer