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Published on: August 8, 2012
HER2-specific T lymphocytes kill both trastuzumab-resistant and trastuzumab-sensitive breast cell lines in vitro
Xiao-Lin Lin1, Xiao-Li Wang, Bo Ma
1Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education), Department of Breast Cancer, Peking University Cancer Hospital & Institute, Beijing 100142, China;
Objective:
Although the development of trastuzumab has improved the outlook for women with human epidermal growth factor receptor 2 (HER2)-positive breast cancer, the resistance to anti-HER2 therapy is a growing clinical dilemma. We aim to determine whether HER2-specific T cells generated from dendritic cells (DCs) modified with HER2 gene could effectively kill the HER2-positive breast cancer cells, especially the trastuzumab-resistant cells.
Methods:
The peripheral blood mononuclear cells (PBMCs) from healthy donors, whose HLA haplotypes were compatible with the tumor cell lines, were transfected with reconstructive human adeno-association virus (rhAAV/HER2) to obtain the specific killing activities of T cells, and were evaluated by lactate dehydrogenase (LDH) releasing assay.
Results:
Trastuzumab produced a significant inhibiting effect on SK-BR-3, the IC50 was 100ng/ml. MDA-MB-453 was resistant to trastuzumab even at a concentration of 10,000 ng/ml in vitro. HER2-specific T lymphocytes killed effectively SK-BR-3 [(69.86±13.41)%] and MDA-MB-453 [(78.36±10.68)%] at 40:1 (effector:target ratio, E:T), but had no significant cytotoxicity against HER2-negative breast cancer cell lines MDA-MB-231 or MCF-7 (less than 10%).
Conclusion:
The study showed that HER2-specific T lymphocytes generated from DCs modified by rhAAV/HER2 could kill HER2-positive breast cancer cell lines in a HER2-dependent manner, and result in significantly high inhibition rates on the intrinsic trastuzumab-resistant cell line MDA-MB-453 and the tastuzumab-sensitive cell line SK-BR-3. These results imply that this immunotherapy might be a potential treatment to HER2-positive breast cancer.
Insights
HER2-specific T cells effectively target HER2-positive breast cancer, including trastuzumab-resistant types. This immunotherapy shows promise for treating HER2-positive breast cancer patients.
Area of Science:
- Immunology
- Oncology
- Biotechnology
Background:
- Trastuzumab therapy improves outcomes for HER2-positive breast cancer.
- Resistance to trastuzumab is a significant clinical challenge.
- Novel therapeutic strategies are needed to overcome anti-HER2 resistance.
Purpose of the Study:
- To evaluate the efficacy of HER2-specific T cells in targeting HER2-positive breast cancer cells.
- To determine if these T cells can overcome trastuzumab resistance.
- To assess the HER2-dependent cytotoxicity of engineered T cells.
Main Methods:
- Peripheral blood mononuclear cells (PBMCs) from healthy donors were genetically modified with HER2 using a viral vector (rhAAV/HER2).
- Dendritic cells (DCs) were engineered to present HER2 antigen to T cells.
- Cytotoxicity was assessed using lactate dehydrogenase (LDH) release assays against various breast cancer cell lines.
Main Results:
- Engineered HER2-specific T lymphocytes demonstrated significant killing of HER2-positive SK-BR-3 cells (69.86%) and trastuzumab-resistant MDA-MB-453 cells (78.36%).
- Cytotoxicity was HER2-dependent, with minimal effect on HER2-negative cell lines (MDA-MB-231, MCF-7).
- Trastuzumab showed efficacy against SK-BR-3 but not MDA-MB-453 in vitro.
Conclusions:
- HER2-specific T cells generated via rhAAV/HER2-modified DCs effectively kill HER2-positive breast cancer cells.
- This approach demonstrates significant inhibition of both trastuzumab-sensitive and resistant cell lines.
- This engineered T-cell immunotherapy presents a potential therapeutic strategy for HER2-positive breast cancer.
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