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Natural Killer T-cell Immunotherapy in Combination with Chemotherapy-Induced Immunogenic Cell Death Targets
Simon Gebremeskel1,2, Lynnea Lobert1,2, Kaitlyn Tanner1
1Department of Microbiology & Immunology, Dalhousie University, Halifax, Nova Scotia, Canada.
Abstract:
Natural killer T (NKT) cells are glycolipid-reactive lymphocytes that promote cancer control. In previous studies, NKT-cell activation improved survival and antitumor immunity in a postsurgical mouse model of metastatic breast cancer. Herein, we investigated whether NKT-cell activation could be combined with chemotherapeutic agents to augment therapeutic outcomes. Gemcitabine and cyclophosphamide analogues enhanced the potential immunogenicity of 4T1 mammary carcinoma cells by increasing the expression of antigen-presenting molecules (MHC-I, MHC-II, and CD1d) and promoting exposure or release of immunogenic cell death markers (calreticulin, HMGB1, and ATP). In 4T1 primary tumor and postsurgical metastasis models, BALB/c mice were treated with cyclophosphamide or gemcitabine. NKT cells were then activated by transfer of dendritic cells loaded with the glycolipid antigen α-galactosylceramide (α-GalCer). Chemotherapeutic treatments did not impact NKT-cell activation but enhanced recruitment into primary tumors. Cyclophosphamide, gemcitabine, or α-GalCer-loaded dendritic cell monotherapies decreased tumor growth in the primary tumor model and reduced metastatic burden and prolonged survival in the metastasis model. Combining chemotherapeutics with NKT-cell activation therapy significantly enhanced survival, with surviving mice exhibiting attenuated tumor growth following a second tumor challenge. The frequency of myeloid-derived suppressor cells was reduced by gemcitabine, cyclophosphamide, or α-GalCer-loaded dendritic cell treatments; cyclophosphamide also reduced the frequency of regulatory T cells. Individual treatments increased immune cell activation, cytokine polarization, and cytotoxic responses, although these readouts were not enhanced further by combining therapies. These findings demonstrate that NKT-cell activation therapy can be combined with gemcitabine or cyclophosphamide to target tumor burden and enhance protection against tumor recurrence. Cancer Immunol Res; 5(12); 1086-97. ©2017 AACR.
Insights
Combining chemotherapy with Natural Killer T (NKT) cell activation therapy enhances survival and protection against breast cancer recurrence in mice. Chemotherapy boosts NKT cell recruitment, improving overall therapeutic outcomes.
Area of Science:
- Immunology
- Cancer Biology
- Pharmacology
Background:
- Natural Killer T (NKT) cells are crucial for anti-cancer immunity.
- Previous research indicated NKT cell activation improves survival in metastatic breast cancer models.
- The potential synergy between NKT cell activation and chemotherapy requires further investigation.
Purpose of the Study:
- To investigate the combined therapeutic effects of NKT cell activation and chemotherapy (gemcitabine, cyclophosphamide) in breast cancer.
- To evaluate the impact of this combination on tumor burden, metastasis, and long-term survival.
- To assess the effects on immune cell populations and anti-tumor responses.
Main Methods:
- 4T1 mammary carcinoma mouse models (primary tumor and postsurgical metastasis) were used.
- Mice were treated with cyclophosphamide or gemcitabine, followed by NKT cell activation via α-galactosylceramide (α-GalCer)-loaded dendritic cells.
- Tumor growth, metastatic burden, survival rates, immune cell frequencies (MDSCs, Tregs), and immune responses were analyzed.
Main Results:
- Chemotherapy enhanced the immunogenicity of 4T1 cells and NKT cell recruitment into tumors.
- Monotherapies (chemotherapy or NKT activation) reduced tumor growth and metastatic burden, prolonging survival.
- Combination therapy significantly enhanced survival and provided protection against tumor recurrence, with reductions in myeloid-derived suppressor cells and regulatory T cells.
Conclusions:
- NKT cell activation therapy can be effectively combined with gemcitabine or cyclophosphamide for breast cancer treatment.
- This combination therapy targets tumor burden and improves protection against recurrence.
- The findings support the development of combined immunochemotherapy strategies for enhanced cancer control.
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