Potenciación de la Inmunoterapia frente al cáncer de pulmón mediante la modulación del microambiente tumoral
Complement C5a has been proposed as a major regulator of myeloid-derived suppressor cells (MDSCs). In this thesis, we aimed to evaluate the mechanisms by which the C5a/C5aR1 axis endows MDSCs with properties that facilitate tumor growth and metastatic spread. Local C5a production in primary tumors s...
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| Format: | info:eu-repo/semantics/doctoralThesis |
| Language: | spa |
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Universidad de Navarra
2021
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| Online Access: | https://hdl.handle.net/10171/61063 |
| _version_ | 1795386265488588800 |
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| author | Ortiz-Espinosa, S. (Sergio) Pio, R. (Rubén) Ajona, D. (Daniel) |
| author_facet | Ortiz-Espinosa, S. (Sergio) Pio, R. (Rubén) Ajona, D. (Daniel) |
| author_sort | Ortiz-Espinosa, S. (Sergio) |
| collection | DSpace |
| description | Complement C5a has been proposed as a major regulator of myeloid-derived suppressor cells (MDSCs). In this thesis, we aimed to evaluate the mechanisms by which the C5a/C5aR1 axis endows MDSCs with properties that facilitate tumor growth and metastatic spread. Local C5a production in primary tumors seems to promote the recruitment of MDSCs, which results in a decrease in the frequency and activity of CD8 T cytotoxic lymphocytes. For this reason, we hypothesized that combined inhibition of C5a/C5aR1 and programmed cell death protein 1 (PD-1) signaling may have a synergistic antitumor effect. Using syngeneic models of lung cancer, we demonstrate that the combined blockade of C5a (AON-D21) and PD-1 (RMP1-14) markedly reduced tumor growth and led to prolonged survival. This effect was accompanied by a negative association between the frequency of CD8 T cells and MDSCs within tumors, which may result in a more complete reversal of CD8 T-cell exhaustion. This study provides support for the clinical evaluation of anti PD-1 and anti-C5a drugs as a novel combination therapeutic strategy for lung cancer. We also characterized the role of C5a on the two distinct subsets of MDSCs: polymorphonuclear MDSCs (PMN-MDSCs) and monocytic MDSCs (MON-MDSCs). Using ex vivo generated MDSCs and antagonists for C5a (AON-D21) and C5aR1 (PMX53), we demonstrate that C5a promoted an integrin-independent amoeboid mode of migration on PMN-MDSCs, while had no apparent effect on MON-MDSCs. In association with the effect on PMN-MDSC migration, C5a downregulated the expression of β1 and β3 integrins (mediators of cell-matrix adhesion) and upregulated the expression of the mediator of leukocyte extravasation CD11b. Moreover, stimulation of PMN-MDSCs with C5a favored the invasion of cancer cells via a process dependent on the extrusion of neutrophil extracellular traps (NETs). C5a/C5aR1 blockade or NET inhibition reduced the number of circulating tumor cells (CTCs) and the metastatic burden in a lung metastasis model. In support of the relevance of these findings obtained in mice, C5a was able to stimulate invasion and NETosis of PMN-MDSCs obtained from lung cancer patients. Moreover, myeloperoxidase (MPO)-DNA complexes, markers of NETosis, were elevated in lung cancer patients and correlated with C5a levels. We conclude that blockade of C5a results in a substantial improvement in the efficacy of anti PD-1 antibodies against lung cancer growth, and that C5a induces the formation of NETs by MDSCs to facilitate the dissemination, colonization and metastasis of cancer cells. |
| format | info:eu-repo/semantics/doctoralThesis |
| id | oai:dadun.unav.edu:10171-61063 |
| institution | Universidad de Navarra |
| language | spa |
| publishDate | 2021 |
| publisher | Universidad de Navarra |
| record_format | dspace |
| spelling | oai:dadun.unav.edu:10171-610632021-07-07T01:05:51Z Potenciación de la Inmunoterapia frente al cáncer de pulmón mediante la modulación del microambiente tumoral Ortiz-Espinosa, S. (Sergio) Pio, R. (Rubén) Ajona, D. (Daniel) Materias Investigacion::Ciencias de la vida::Citología, biología celular Materias Investigacion::Ciencias de la Salud::Inmunología Materias Investigacion::Ciencias de la Salud::Oncología Cáncer de pulmón Inmunoterapia Complement C5a has been proposed as a major regulator of myeloid-derived suppressor cells (MDSCs). In this thesis, we aimed to evaluate the mechanisms by which the C5a/C5aR1 axis endows MDSCs with properties that facilitate tumor growth and metastatic spread. Local C5a production in primary tumors seems to promote the recruitment of MDSCs, which results in a decrease in the frequency and activity of CD8 T cytotoxic lymphocytes. For this reason, we hypothesized that combined inhibition of C5a/C5aR1 and programmed cell death protein 1 (PD-1) signaling may have a synergistic antitumor effect. Using syngeneic models of lung cancer, we demonstrate that the combined blockade of C5a (AON-D21) and PD-1 (RMP1-14) markedly reduced tumor growth and led to prolonged survival. This effect was accompanied by a negative association between the frequency of CD8 T cells and MDSCs within tumors, which may result in a more complete reversal of CD8 T-cell exhaustion. This study provides support for the clinical evaluation of anti PD-1 and anti-C5a drugs as a novel combination therapeutic strategy for lung cancer. We also characterized the role of C5a on the two distinct subsets of MDSCs: polymorphonuclear MDSCs (PMN-MDSCs) and monocytic MDSCs (MON-MDSCs). Using ex vivo generated MDSCs and antagonists for C5a (AON-D21) and C5aR1 (PMX53), we demonstrate that C5a promoted an integrin-independent amoeboid mode of migration on PMN-MDSCs, while had no apparent effect on MON-MDSCs. In association with the effect on PMN-MDSC migration, C5a downregulated the expression of β1 and β3 integrins (mediators of cell-matrix adhesion) and upregulated the expression of the mediator of leukocyte extravasation CD11b. Moreover, stimulation of PMN-MDSCs with C5a favored the invasion of cancer cells via a process dependent on the extrusion of neutrophil extracellular traps (NETs). C5a/C5aR1 blockade or NET inhibition reduced the number of circulating tumor cells (CTCs) and the metastatic burden in a lung metastasis model. In support of the relevance of these findings obtained in mice, C5a was able to stimulate invasion and NETosis of PMN-MDSCs obtained from lung cancer patients. Moreover, myeloperoxidase (MPO)-DNA complexes, markers of NETosis, were elevated in lung cancer patients and correlated with C5a levels. We conclude that blockade of C5a results in a substantial improvement in the efficacy of anti PD-1 antibodies against lung cancer growth, and that C5a induces the formation of NETs by MDSCs to facilitate the dissemination, colonization and metastasis of cancer cells. 2021-07-06T10:51:05Z 2021-07-06T10:51:05Z 2021-07-06 2021-02-05 info:eu-repo/semantics/doctoralThesis https://hdl.handle.net/10171/61063 spa info:eu-repo/semantics/embargoedAccess application/pdf Universidad de Navarra |
| spellingShingle | Materias Investigacion::Ciencias de la vida::Citología, biología celular Materias Investigacion::Ciencias de la Salud::Inmunología Materias Investigacion::Ciencias de la Salud::Oncología Cáncer de pulmón Inmunoterapia Ortiz-Espinosa, S. (Sergio) Pio, R. (Rubén) Ajona, D. (Daniel) Potenciación de la Inmunoterapia frente al cáncer de pulmón mediante la modulación del microambiente tumoral |
| title | Potenciación de la Inmunoterapia frente al cáncer de pulmón mediante la modulación del microambiente tumoral |
| title_full | Potenciación de la Inmunoterapia frente al cáncer de pulmón mediante la modulación del microambiente tumoral |
| title_fullStr | Potenciación de la Inmunoterapia frente al cáncer de pulmón mediante la modulación del microambiente tumoral |
| title_full_unstemmed | Potenciación de la Inmunoterapia frente al cáncer de pulmón mediante la modulación del microambiente tumoral |
| title_short | Potenciación de la Inmunoterapia frente al cáncer de pulmón mediante la modulación del microambiente tumoral |
| title_sort | potenciación de la inmunoterapia frente al cáncer de pulmón mediante la modulación del microambiente tumoral |
| topic | Materias Investigacion::Ciencias de la vida::Citología, biología celular Materias Investigacion::Ciencias de la Salud::Inmunología Materias Investigacion::Ciencias de la Salud::Oncología Cáncer de pulmón Inmunoterapia |
| url | https://hdl.handle.net/10171/61063 |
| work_keys_str_mv | AT ortizespinosassergio potenciaciondelainmunoterapiafrentealcancerdepulmonmediantelamodulaciondelmicroambientetumoral AT piorruben potenciaciondelainmunoterapiafrentealcancerdepulmonmediantelamodulaciondelmicroambientetumoral AT ajonaddaniel potenciaciondelainmunoterapiafrentealcancerdepulmonmediantelamodulaciondelmicroambientetumoral |