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Published on: March 17, 2020
Immunological hallmarks of cis-DDP-resistant Lewis lung carcinoma cells
Olexandr Fedorchuk1, Yaroslav Susak2, Mariia Rudyk3
1R. E. Kavetsky Institute of Experimental Pathology, Oncology and Radiobiology, National Academy of Sciences of Ukraine, Kyiv, Ukraine.
Purpose:
Tumor cell resistance to platinum-based chemotherapeutic agents is one of the major hurdles to successful cancer treatment with these drugs, and is associated with alterations in tumor cell immune evasion and immunomodulatory properties. Immunocyte targeting is considered as a relevant approach to fight drug-resistant cancer. In this study, immunological hallmarks of cis-DDP-resistant Lewis lung carcinoma cells (LLC/R9) were investigated.
Methods:
Immunological features of LLC/R9 cells cultured in vitro in normoxic and hypoxic conditions as well as of those that were grown in vivo were examined. The expression of immunologically relevant genes was evaluated by RT-PCR. Tumor cell susceptibility to the macrophage contact tumoricidal activity and NK-mediated cytolysis was investigated in MTT test. TNF-α-mediated tumor cell apoptosis as well as macrophage phagocytosis, oxidative metabolism, and CD206 expression after the treatment with conditioned media from normoxic and hypoxic tumor cells were studied by flow cytometry. Flow cytometry was also used to characterize dendritic cell maturity.
Results:
When growing in vitro, LLC/R9 were characterized by slightly increased immunosuppressive cytokine gene expression. Transition to in vivo growth was associated with the enhancement of transcription of these genes in tumor cells. LLC/R9 cells had lowered sensitivity to contact-dependent macrophage-mediated cytotoxicity and to the TNFα-mediated apoptosis in vitro. Conditioned media from hypoxic LLC/R9 cells stimulated reactive oxygen species generation and CD206 expression in non-sensitized macrophages. Acquisition of drug resistance by LLC/R9 cells was associated with their increased sensitivity to NK-cell-mediated cytolysis. Meanwhile, the treatment of LLCR/9-bearing animals with generated ex vivo and loaded with LLC/R9 cell-lysate dendritic cells (DCs) resulted in profoundly enhanced tumor metastasizing.
Conclusion:
Decreased sensitivity to macrophage cytolysis, polarizing effect on DCs maturation along with increased susceptibility to NK-cell cytotoxic action promote extensive local growth of chemoresistant LLC/R9 tumors in vivo, but hamper their metastasizing.
Insights
Drug-resistant lung cancer cells evade macrophages but become more sensitive to natural killer cells. This immune evasion promotes local tumor growth but hinders metastasis.
Area of Science:
- Immunology
- Cancer Research
- Drug Resistance
Background:
- Tumor cell resistance to platinum-based chemotherapy is a major obstacle in cancer treatment.
- This resistance is linked to tumor cells' altered immune evasion and immunomodulatory properties.
- Targeting immune cells is a promising strategy against drug-resistant cancers.
Purpose of the Study:
- To investigate the immunological characteristics of cisplatin-resistant Lewis lung carcinoma cells (LLC/R9).
- To understand how these cells interact with immune cells in different conditions (in vitro, in vivo, normoxic, hypoxic).
Main Methods:
- LLC/R9 cells were cultured in vitro (normoxic/hypoxic) and grown in vivo.
- Gene expression of immunologically relevant factors was analyzed using RT-PCR.
- Susceptibility to macrophage cytotoxicity, NK-cell-mediated lysis, and TNF-α-induced apoptosis was assessed.
- Macrophage functions (phagocytosis, oxidative metabolism, CD206 expression) and dendritic cell (DC) maturity were evaluated by flow cytometry.
Main Results:
- LLC/R9 cells exhibited increased immunosuppressive cytokine gene expression in vitro, further enhanced in vivo.
- These cells showed reduced sensitivity to macrophage-mediated cytotoxicity and TNF-α-induced apoptosis.
- Hypoxic LLC/R9 conditioned media promoted reactive oxygen species generation and CD206 expression in macrophages.
- Drug-resistant LLC/R9 cells displayed increased sensitivity to NK-cell-mediated cytolysis.
- Treatment with LLC/R9 lysate-loaded DCs in tumor-bearing animals led to enhanced tumor metastasizing.
Conclusions:
- Reduced sensitivity to macrophage lysis and altered DC maturation, coupled with heightened NK-cell susceptibility, contribute to the extensive local growth of chemoresistant LLC/R9 tumors.
- These immune interactions paradoxically inhibit tumor metastasis in vivo.
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