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  • 1
    Online Resource
    Online Resource
    Blocking Migration of Polymorphonuclear Myeloid-Derived Suppressor Cells Inhibits Mouse Melanoma Progression
    MDPI AG ; 2021
    In:  Cancers Vol. 13, No. 4 ( 2021-02-10), p. 726-
    Details
    In: Cancers, MDPI AG, Vol. 13, No. 4 ( 2021-02-10), p. 726-
    Abstract: Background: Despite recent improvement in the treatment of malignant melanoma by immune-checkpoint inhibitors, the disease can progress due to an immunosuppressive tumor microenvironment (TME) mainly represented by myeloid-derived suppressor cells (MDSC). However, the relative contribution of the polymorphonuclear (PMN) and monocytic (M) MDSC subsets to melanoma progression is not clear. Here, we compared both subsets regarding their immunosuppressive capacity and recruitment mechanisms. Furthermore, we inhibited PMN-MDSC migration in vivo to determine its effect on tumor progression. Methods: Using the RET transgenic melanoma mouse model, we investigated the immunosuppressive function of MDSC subsets and chemokine receptor expression on these cells. The effect of CXCR2 inhibition on PMN-MDSC migration and tumor progression was studied in RET transgenic mice and in C57BL/6 mice after surgical resection of primary melanomas. Results: Immunosuppressive capacity of intratumoral M- and PMN-MDSC was comparable in melanoma bearing mice. Anti-CXCR2 therapy prolonged survival of these mice and decreased the occurrence of distant metastasis. Furthermore, this therapy reduced the infiltration of melanoma lesions and pre-metastatic sites with PMN-MDSC that was associated with the accumulation of natural killer (NK) cells. Conclusions: We provide evidence for the tumor−promoting properties of PMN-MDSC as well as for the anti-tumor effects upon their targeting in melanoma bearing mice.
    Type of Medium: Online Resource
    ISSN: 2072-6694
    URL: Article
    DOI: 10.3390/cancers13040726
    Language: English
    Publisher: MDPI AG
    Publication Date: 2021
    detail.hit.zdb_id: 2527080-1
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  • 2
    Online Resource
    Online Resource
    The Bilateral Interplay between Cancer Immunotherapies and Neutrophils’ Phenotypes and Sub-Populations
    MDPI AG ; 2022
    In:  Cells Vol. 11, No. 5 ( 2022-02-23), p. 783-
    Details
    In: Cells, MDPI AG, Vol. 11, No. 5 ( 2022-02-23), p. 783-
    Abstract: Immunotherapy has become a leading modality for the treatment of cancer, but despite its increasing success, a substantial number of patients do not benefit from it. Cancer-related neutrophils have become, in recent years, a subject of growing interest. Distinct sub-populations of neutrophils have been identified at advanced stages of cancer. In this study, we aimed to evaluate the role of neutrophils in mediating the efficacy of immune checkpoint inhibitors (ICI) treatments (α-PD-1/PD-L1), by assessing lung tumor models in mice. We found that G-CSF overexpression by the tumor significantly potentiates the efficacy of ICI, whereas neutrophils’ depletion abrogated their responses. Adoptive transfer of circulating normal-density neutrophils (NDN) resulted in significantly reduced tumor growth, whereas low-density neutrophils (LDN) had no effect. We next investigated the effect of ICI on neutrophils’ functions. Following α-PD-L1 treatment, NDN displayed increased ROS production and increased cytotoxicity toward tumor cells but decreased degranulation. Together, our results suggest that neutrophils are important mediators of the ICI treatments and that mainly NDN are modulated following α-PD-L1 treatment. This research provides a better understanding of the function of neutrophils following immunotherapies and their impact on the efficacy of immunotherapy, supporting better understanding and future improvement of currently available treatments.
    Type of Medium: Online Resource
    ISSN: 2073-4409
    URL: Article
    DOI: 10.3390/cells11050783
    Language: English
    Publisher: MDPI AG
    Publication Date: 2022
    detail.hit.zdb_id: 2661518-6
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  • 3
    Online Resource
    Online Resource
    How Accurate Is the Diagnosis of “Chronic Obstructive Pulmonary Disease” in Patients Hospitalized with an Acute Exacerbation?
    MDPI AG ; 2023
    In:  Medicina Vol. 59, No. 3 ( 2023-03-22), p. 632-
    Details
    In: Medicina, MDPI AG, Vol. 59, No. 3 ( 2023-03-22), p. 632-
    Abstract: Rationale: COPD diagnosis requires relevant symptoms and an FEV1/FVC ratio of 〈 0.7 post-bronchodilator on spirometry. Patients are frequently labeled as COPD based on clinical presentation and admitted to the hospital with this diagnosis even though spirometry is either not available or has never been performed. The aim of this study was to evaluate the accuracy of COPD diagnosis based on post-bronchodilator spirometry, following hospital admission for COPD exacerbation. Methods: This is a retrospective study with a cross-sectional analysis of a subgroup of patients. Demographic and clinical data and pre-admission spirometry were collected from electronic records of patients hospitalized with a primary diagnosis of COPD. Patients without available spirometry were contacted for a pulmonary consultation and spirometry. Three groups were compared: patients with a confirmed COPD diagnosis (FEV1/FVC 〈 0.7), without COPD (FEV1/FVC 〉 0.7), and those who have never performed spirometry. Results: A total of 1138 patients with a recorded diagnosis of COPD were identified of which 233 patients were included in the analysis. Only 44.6% of patients had confirmed COPD according to GOLD criteria. In total, 32.6% of the patients had never undergone spirometry but were treated as COPD, and 22.7% had performed spirometry without evidence of COPD. Recurrent admission due to COPD was a strong predictor of a confirmed COPD diagnosis. Conclusions: Among the patients admitted to the hospital with a COPD diagnosis, a high proportion were not confirmed by the current GOLD report or had never performed spirometry. Stricter implementation of the diagnostic criteria of COPD in admitted patients is necessary to improve diagnosis and the treatment outcomes in these patients.
    Type of Medium: Online Resource
    ISSN: 1648-9144
    URL: Article
    DOI: 10.3390/medicina59030632
    Language: English
    Publisher: MDPI AG
    Publication Date: 2023
    detail.hit.zdb_id: 2088820-X
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  • 4
    Online Resource
    Online Resource
    Tumor-Derived Factors Differentially Affect the Recruitment and Plasticity of Neutrophils
    MDPI AG ; 2021
    In:  Cancers Vol. 13, No. 20 ( 2021-10-11), p. 5082-
    Details
    In: Cancers, MDPI AG, Vol. 13, No. 20 ( 2021-10-11), p. 5082-
    Abstract: Neutrophils play a key role in cancer biology. In contrast to circulating normal-density neutrophils (NDN), the amount of low-density neutrophils (LDN) significantly increases with tumor progression. The correlation between these neutrophil subpopulations and intratumoral neutrophils (TANs) is still under debate. Using 4T1 (breast) and AB12 (mesothelioma) tumor models, we aimed to elucidate the source of TANs and to assess the mechanisms driving neutrophils’ plasticity in cancer. Both NDN and LDN were found to migrate in response to CXCL1 and CXCL2 exposure, and co-infiltrate the tumor site ex vivo and in vivo, although LDN migration into the tumor was higher than NDN. Tumor-derived factors and chemokines, particularly CXCL1, were found to drive neutrophil phenotypical plasticity, inducing NDN to transition towards a low-density state (LD-NDN). LD-NDN appeared to differ from NDN by displaying a phenotypical profile similar to LDN in terms of nuclear morphology, surface receptor markers, decreased phagocytic abilities, and increased ROS production. Interestingly, all three subpopulations displayed comparable cytotoxic abilities towards tumor cells. Our data suggest that TANs originate from both LDN and NDN, and that a portion of LDN derives from NDN undergoing phenotypical changes. NDN plasticity resulted in a change in surface marker expression and functional activity, gaining characteristics of LDN.
    Type of Medium: Online Resource
    ISSN: 2072-6694
    URL: Article
    DOI: 10.3390/cancers13205082
    Language: English
    Publisher: MDPI AG
    Publication Date: 2021
    detail.hit.zdb_id: 2527080-1
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  • 5
    Online Resource
    Online Resource
    RNA Sequencing Reveals Unique Transcriptomic Signatures of the Thyroid in a Murine Lung Cancer Model Treated with PD-1 and PD-L1 Antibodies
    MDPI AG ; 2023
    In:  International Journal of Molecular Sciences Vol. 24, No. 13 ( 2023-06-23), p. 10526-
    Details
    In: International Journal of Molecular Sciences, MDPI AG, Vol. 24, No. 13 ( 2023-06-23), p. 10526-
    Abstract: Immune checkpoint inhibitors (ICI) are commonly associated with thyroid immune-related adverse events, yet the mechanism has not been fully elucidated. We aimed to further explore the mechanism of ICI-induced thyroid dysfunction by assessing changes induced in the thyroid transcriptome by ICI treatment (αPD-1/αPD-L1) in a lung cancer murine model. RNA-sequencing of thyroid tissues revealed 952 differentially expressed genes (DEGs) with αPD-1 treatment (|fold-change| ≥1.8, FDR 〈 0.05). Only 35 DEG were identified with αPD-L1, and we therefore focused on the αPD-1 group alone. Ingenuity Pathway Analysis revealed that of 952 DEGs with αPD-1 treatment, 362 were associated with functions of cell death and survival, with predicated activation of pathways for apoptosis and necrosis (Z = 2.89 and Z = 3.21, respectively) and negative activation of pathways for cell viability and cell survival (Z = −6.22 and Z = −6.45, respectively). Compared to previously published datasets of interleukin-1β and interferon γ-treated human thyroid cells, apoptosis pathways were similarly activated. However, unique changes related to organ inflammation and upstream regulation by cytokines were observed. Our data suggest that there are unique changes in gene expression in the thyroid associated with αPD-1 therapy. ICI-induced thyroid dysfunction may be mediated by increased tissue apoptosis resulting in destructive thyroiditis.
    Type of Medium: Online Resource
    ISSN: 1422-0067
    URL: Article
    DOI: 10.3390/ijms241310526
    Language: English
    Publisher: MDPI AG
    Publication Date: 2023
    detail.hit.zdb_id: 2019364-6
    SSG: 12
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