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Mechanisms of immune response regulation in lung cancer
Joanna Domagala-Kulawik1, Iwona Osinska1, Grazyna Hoser1
11 Department of Internal Diseases, Pneumonology and Allergology, Medical University of Warsaw, Warsaw, Poland ; 2 Department of Pathology, Medical University of Warsaw, Warsaw, Poland ; 3 Laboratory of Flow Cytometry, Medical Center of Postgraduate Education, Warsaw, Poland.
Abstract:
Lung cancer is a leading cause of cancer deaths. As a solid tumor with low antigenicity and heterogenic phenotype lung cancer evades host immune defense. The cytotoxic anticancer effect is suppressed by a complex mechanism in tumor microenvironment. The population of regulatory T cells (Tregs) plays a crucial role in this inhibition of immune response. Tregs are defined by presence of forkhead box P3 (Foxp3) molecule. The high expression of Foxp3 was found in lung cancer cells and in tumor infiltrating lymphocytes (TIL). Cytotoxic T-lymphocyte antigen 4 (CTLA4) is constitutively expressed on Tregs and suppresses T cell activation. The elevated CTLA4 expression in lymphocytes in patients with lung cancer was found. Recently the antibodies blocking CTLA4 showed some clinical efficacy in patients with lung cancer. Cancer cells and immune cells release many cytokines capable to show suppressive immune effect in cancer microenvironment. The most active are transforming growth factorβ (TGFβ) and IL-10. The pleiotropic function of Th17 population is TGFβ related. The myeloid lineage of suppressor cells in lung cancer is represented by tumor associated macrophages (TAM) with phenotype of M2 macrophages and some regulatory properties with releasing amounts of IL-10 and TGFβ. The myeloid derived suppressor cells (MDSCs) control cytotoxic T cell activity in mechanisms which are highly dependent on the context of tumor environment. The mechanisms of anticancer immune response regulation need further investigation as an important target to new way of treatment.
Insights
Regulatory T cells (Tregs) and other immune suppressors hinder anti-lung cancer immunity. Targeting these pathways, like CTLA-4, offers potential for new lung cancer treatments.
Area of Science:
- Oncology
- Immunology
Background:
- Lung cancer is a major cause of cancer mortality.
- Solid tumors like lung cancer often evade immune defense due to low antigenicity and heterogeneity.
- The tumor microenvironment employs complex mechanisms to suppress cytotoxic anti-cancer immune responses.
Purpose of the Study:
- To investigate the mechanisms of immune suppression in the lung cancer tumor microenvironment.
- To identify key immune cell populations and molecular factors involved in evading host immune defense against lung cancer.
- To explore potential therapeutic targets for enhancing anti-cancer immunity in lung cancer.
Main Methods:
- Analysis of regulatory T cells (Tregs) expressing forkhead box P3 (Foxp3).
- Assessment of Cytotoxic T-lymphocyte antigen 4 (CTLA4) expression on lymphocytes.
- Evaluation of cytokine profiles, including transforming growth factor-beta (TGFβ) and IL-10.
- Characterization of myeloid-derived suppressor cells (MDSCs) and tumor-associated macrophages (TAMs).
Main Results:
- High expression of Foxp3 was observed in lung cancer cells and tumor-infiltrating lymphocytes (TIL).
- Elevated CTLA4 expression was found in lymphocytes of lung cancer patients.
- Immune suppressive cytokines like TGFβ and IL-10 are prevalent in the tumor microenvironment.
- MDSCs and M2-phenotype TAMs contribute to immune suppression by regulating cytotoxic T cell activity.
Conclusions:
- Regulatory T cells (Tregs) and myeloid-derived suppressor cells (MDSCs) play significant roles in suppressing anti-cancer immunity in lung cancer.
- Targeting CTLA-4 has shown clinical efficacy, suggesting its potential as a therapeutic strategy.
- Further investigation into the intricate mechanisms of immune regulation in lung cancer is crucial for developing novel treatments.
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