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Dreyer, T.F.* ; Kühn, S.* ; Stange, C.* ; Heithorst, N.* ; Schilling, D. ; Jelsma, J.* ; Sievert, W.* ; Seitz, S.* ; Stangl, S.* ; Hapfelmeier, A.* ; Noske, A.* ; Wege, A.K.* ; Weichert, W.* ; Ruland, J.* ; Schmitt, M.* ; Dorn, J.* ; Kiechle, M.* ; Reuning, U.* ; Magdolen, V.* ; Multhoff, G.* ; Bronger, H.*

The chemokine CX3CL1 improves trastuzumab efficacy in HER2 low-expressing cancer in vitro and in vivo.

Cancer Immunol. Res. 9, 779-789 (2021)
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A crucial mode of action of trastuzumab is the labeling of HER2-positive (HER2(+)) tumor cells for the eradication by natural killer (NK) cells, a process called antibody-dependent cellular cytotoxicity (ADCC). However, despite widespread HER2 expression among cancer entities, only a fraction, with robust HER2 overexpression, benefits from trastuzumab therapy. ADCC requires both sufficient lymphocytic infiltration and close binding of the immune cells to the antibody-tagged tumor cells. We hypothesized that the chemokine CX3CL1 could improve both processes, as it is synthesized as a membrane-bound, adhesive form that is eventually cleaved into a soluble, chemotactic protein. Here, we show that CX3CL1 overexpression is a positive prognostic marker in breast cancer. CX3CL1 overexpression attracted tumor-suppressive lymphocytes, including NK cells, and inhibited tumor growth and lung metastasis in the syngeneic 4T1 breast cancer mouse model. In HER2(+) SKBR3, MDA-MB-453, and HT-29 tumor cells, CX3CL1 overexpression increased NK cellmediated cytotoxicity in vitro and acted synergistically with trastuzumab. Even though CX3CL1 did not further improve trastuzumab efficacy in vivo in the trastuzumab-sensitive MDA-MB-453 model, it compensated for NK-cell depletion and prolonged survival. In the HER2 low-expressing HT-29 model, however, CX3CL1 overexpression not only prolonged survival time but also overcame trastuzumab resistance in a partly NK cell-dependent manner. Taken together, these findings identify CX3CL1 as a feasible pharmacologic target to enable trastuzumab therapy in HER2 low-expressing cancers and render it a potential predictive biomarker to determine therapy responders.
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Publication type Article: Journal article
Document type Scientific Article
Keywords Natural-killer-cells; Tumor-infiltrating Lymphocytes; Breast-cancer; T-cells; Antitumor Immunity; Poor-prognosis; Ifn-gamma; Fractalkine; Receptors; Survival
Language english
Publication Year 2021
HGF-reported in Year 2021
ISSN (print) / ISBN 2326-6066
e-ISSN 2326-6074
Journal Cancer Immunology Research
Quellenangaben Volume: 9, Issue: 7, Pages: 779-789 Article Number: , Supplement: ,
Publisher AACR
Publishing Place Philadelphia, Pa.
Reviewing status Peer reviewed
Institute(s) Institute of Radiation Medicine (IRM)
POF-Topic(s) 30203 - Molecular Targets and Therapies
Research field(s) Radiation Sciences
PSP Element(s) G-501300-001
Grants German Research Foundation (Deutsche Forschungsgemeinschaft, DFG)
DOI 10.1158/2326-6066.CIR-20-0327
WOS ID WOS:000670532600007
PubMed ID 33906866
Erfassungsdatum 2021-08-02
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