| Item type: | Article | ||||
|---|---|---|---|---|---|
| Journal or Publication Title: | Cancer Immunology Research | ||||
| Publisher: | AMER ASSOC CANCER RESEARCH | ||||
| Place of Publication: | PHILADELPHIA | ||||
| Volume: | 9 | ||||
| Number of Issue or Book Chapter: | 7 | ||||
| Page Range: | pp. 779-789 | ||||
| Date: | 2021 | ||||
| Institutions: | Medicine > Lehrstuhl für Frauenheilkunde und Geburtshilfe (Schwerpunkt Frauenheilkunde) | ||||
| Identification Number: |
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| Keywords: | NATURAL-KILLER-CELLS; TUMOR-INFILTRATING LYMPHOCYTES; BREAST-CANCER; T-CELLS; ANTITUMOR IMMUNITY; POOR-PROGNOSIS; IFN-GAMMA; FRACTALKINE; RECEPTORS; SURVIVAL; | ||||
| Dewey Decimal Classification: | 600 Technology > 610 Medical sciences Medicine | ||||
| Status: | Published | ||||
| Refereed: | Yes, this version has been refereed | ||||
| Created at the University of Regensburg: | Yes | ||||
| Item ID: | 56505 |
Web of ScienceAbstract
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 ...
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 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.
Metadata last modified: 29 Feb 2024 12:28
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