The chemokine CX3CL1 improves trastuzumab efficacy in HER2 low-expressing cancer in vitro and in vivo
| Autor: | Viktor Magdolen, Nadine Heithorst, Alexander Hapfelmeier, Manfred Schmitt, Wolfgang Sievert, Aurelia Noske, Anja K Wege, Ute Reuning, Tobias Dreyer, Sabine Kuhn, Julia Dorn, Stefanie Seitz, Jil Jelsma, Christoph Stange, Wilko Weichert, Holger Bronger, Gabriele Multhoff, Marion Kiechle, Stefan Stangl, Jürgen Ruland, Daniela Schilling |
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| Jazyk: | angličtina |
| Rok vydání: | 2021 |
| Předmět: |
0301 basic medicine
Antibody-dependent cell-mediated cytotoxicity Cancer Research Chemokine biology business.industry Immunology Cancer medicine.disease 03 medical and health sciences 030104 developmental biology 0302 clinical medicine Immune system SKBR3 In vivo Trastuzumab 030220 oncology & carcinogenesis biology.protein Cancer research Medicine skin and connective tissue diseases business CX3CL1 neoplasms medicine.drug |
| Zdroj: | Cancer Immunol. Res. 9, 779-789 (2021) |
| Popis: | 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 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. |
| Databáze: | OpenAIRE |
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