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

Abstract

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.

• Authors: Tobias F Dreyer, Sabine Kuhn, Christoph Stange, Nadine Heithorst, Daniela Schilling, Jil Jelsma, Wolfgang Sievert, Stefanie Seitz, Stefan Stangl, Alexander Hapfelmeier, Aurelia Noske, Anja K Wege, Wilko Weichert, Jürgen Ruland, Manfred Schmitt, Julia Dorn, Marion Kiechle, Ute Reuning, Viktor Magdolen, Gabriele Multhoff, Holger Bronger
• Journal: Cancer immunology research (Cancer Immunol Res) Vol. 9 Issue 7 Pg. 779-789 (07 2021) ISSN: 2326-6074 [Electronic] United States
• PMID: 33906866 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: ©2021 American Association for Cancer Research.

Chemical References

• Antineoplastic Agents, Immunological
• CX3CL1 protein, human
• Chemokine CX3CL1
• Cx3cl1 protein, mouse
• ERBB2 protein, human
• Erbb2 protein, mouse
• Receptor, ErbB-2
• Trastuzumab

Topics

• Adult
• Aged
• Aged, 80 and over
• Animals
• Antineoplastic Agents, Immunological (pharmacology, therapeutic use)
• Breast Neoplasms (drug therapy, mortality, pathology)
• Chemokine CX3CL1 (genetics, metabolism)
• Cohort Studies
• Drug Resistance, Neoplasm (genetics, immunology)
• Female
• Gene Expression Profiling
• Gene Expression Regulation, Neoplastic (immunology)
• Humans
• Kaplan-Meier Estimate
• Killer Cells, Natural (immunology)
• Lung Neoplasms (drug therapy, secondary)
• Mice
• Middle Aged
• Prognosis
• Receptor, ErbB-2 (analysis, antagonists & inhibitors, metabolism)
• Signal Transduction (immunology)
• Trastuzumab (pharmacology, therapeutic use)
• Tumor Microenvironment (genetics, immunology)
• Young Adult