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Selected Publication:
Valadez Cosmes, P.
New insights into the role of neutrophils in non-small cell lung cancer: the case of low-density neutrophils and myeloperoxidase
PhD-Studium (Doctor of Philosophy); Humanmedizin; [ Dissertation ] Medizinische Universität Graz; 2024. pp. 123
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- Authors Med Uni Graz:
- Advisor:
- Höfler Gerald
- Kargl Julia
- Sattler Wolfgang
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- Abstract:
- Lung cancer is the most frequently diagnosed type of cancer and tops the list of deadliest cancers around the world. Non-small cell lung cancer (NSCLC) leads the diagnoses and represents about 85% of all lung cancer cases. Neutrophils are heterogeneous and versatile cells that contribute to tumor development. They are especially abundant within the tumor microenvironment (TME) of NSCLC and have shown to exert pro-tumorigenic actions favoring NSCLC development. Moreover, specific circulating neutrophil populations have been identified in the blood of cancer patients and have been proposed to depict immune-suppressive actions. Despite this, the mechanisms by which neutrophils exert their actions in NSCLC are not completely elucidated yet and the classification of neutrophil subpopulations in circulation and in the tumor is still a major field to explore. The present thesis is divided in two independent projects that aimed to address the role of neutrophils in NSCLC from two different perspectives: - In the first project we used a high-dimensional human cell surface marker screen to identify cellular markers that allow us to discriminate between two circulating neutrophil populations; the so-called low-density neutrophils (LDNs) and high-density neutrophils (HDNs). Using this approach, we categorized 12 surface markers as low expressed by LDNs vs HDNs, while 41 surface markers were highly expressed in the LDN subset vs the HDN. We designed a specific flow cytometry panel that allowed us to validate the overexpression of CD36, CD41, CD61 and CD226 in the LDN fraction. Moreover, we confirmed the exclusive existence of LDNs in the blood of NSCLC patients while they were almost absent in the blood of healthy donors. - In the second project, we investigated the role of a neutrophil-derived enzyme called myeloperoxidase (MPO) in the development of NSCLC. Using a heterotopic NSCLC model in MPO-deficient mice, we observed a reduction of tumor growth that was accompanied by an increase in the infiltration of cytotoxic T cells when compared to WT mice. CD8 depletion abolished the previously observed reduction in tumor size in MPO KO mice, indicating that CD8+ T cells play an important role. In vitro, MPO addition to T cells resulted in decreased proliferation and activation of T cells. Moreover, MPO was internalized into T cells, while heparin pre-treatment blocked MPO internalization and reversed the anti-proliferative effect of MPO in T cells. Interestingly, MPO+ lymphocytes were found in tumor samples from patients with NSCLC while an in silico analysis showed a survival benefit in patients with NSCLC and low MPO expression. In summary, our findings highlight the importance of neutrophils and neutrophil-derived enzymes in the biology of lung cancer and contribute to the understanding of the complex roles of these cells in cancer. Altogether, this dissertation offers ideas of how neutrophils and their molecules are potential candidates that can be used as diagnostic tools and therapeutic targets.