The Chemokine CX3CL1 Improves Trastuzumab Efficacy in HER2 Low-Expressing Cancer In Vitro and In Vivo

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 ro...

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Bibliographic Details
Published in:Cancer immunology research 2021-07, Vol.9 (7), p.779-789
Main Authors: Dreyer, Tobias F, Kuhn, Sabine, Stange, Christoph, Heithorst, Nadine, Schilling, Daniela, Jelsma, Jil, Sievert, Wolfgang, Seitz, Stefanie, Stangl, Stefan, Hapfelmeier, Alexander, Noske, Aurelia, Wege, Anja K, Weichert, Wilko, Ruland, Jürgen, Schmitt, Manfred, Dorn, Julia, Kiechle, Marion, Reuning, Ute, Magdolen, Viktor, Multhoff, Gabriele, Bronger, Holger
Format: Article
Language:English
Subjects:
Adult
Aged
Aged, 80 and over
Animals
Antineoplastic Agents, Immunological - pharmacology
Antineoplastic Agents, Immunological - therapeutic use
Breast Neoplasms - drug therapy
Breast Neoplasms - mortality
Breast Neoplasms - pathology
Chemokine CX3CL1 - genetics
Chemokine CX3CL1 - metabolism
Cohort Studies
Drug Resistance, Neoplasm - genetics
Drug Resistance, Neoplasm - immunology
Female
Gene Expression Profiling
Gene Expression Regulation, Neoplastic - immunology
Humans
Kaplan-Meier Estimate
Killer Cells, Natural - immunology
Lung Neoplasms - drug therapy
Lung Neoplasms - secondary
Mice
Middle Aged
Prognosis
Receptor, ErbB-2 - analysis
Receptor, ErbB-2 - antagonists & inhibitors
Receptor, ErbB-2 - metabolism
Signal Transduction - immunology
Trastuzumab - pharmacology
Trastuzumab - therapeutic use
Tumor Microenvironment - genetics
Tumor Microenvironment - immunology
Young Adult
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Summary: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 cell-mediated cytotoxicity and acted synergistically with trastuzumab. Even though CX3CL1 did not further improve trastuzumab efficacy 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.
ISSN:2326-6066
2326-6074
DOI:10.1158/2326-6066.CIR-20-0327