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postgraduate thesis: The role and mechanisms of interleukin-9 in facilitating anticancer effect of immune checkpoint blockade in lung cancer animal model
Title | The role and mechanisms of interleukin-9 in facilitating anticancer effect of immune checkpoint blockade in lung cancer animal model |
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Authors | |
Advisors | |
Issue Date | 2023 |
Publisher | The University of Hong Kong (Pokfulam, Hong Kong) |
Citation | Feng, Y. [馮玉倩]. (2023). The role and mechanisms of interleukin-9 in facilitating anticancer effect of immune checkpoint blockade in lung cancer animal model. (Thesis). University of Hong Kong, Pokfulam, Hong Kong SAR. |
Abstract | Lung cancer remains the major reason for cancer-related deaths. Immune checkpoint blockade (ICB), particularly with the use of programmed cell death protein 1 (PD-1)/programmed cell death protein ligand 1 (PD-L1) antibodies, has gained major advancement in cancer therapy throughout the recent decade, nonetheless only a minority of patients may benefit. Therefore, novel immunotherapeutic targets and combination strategies are urgently needed to
II
expand the clinical benefit to wider patient population. Interleukin-9 (IL-9) is known to be important in modifying tumor biology and has pleiotropic effects in different cancers. In lung cancer, the function of IL-9 is not fully elucidated. The purpose of this study was to better understand the function(s) of IL-9 in lung cancer and the underlying mechanisms.
Lewis lung carcinoma (LLC) and CMT167 murine lung cancer cell lines were utilized in this study. IL-9 receptor (IL-9R) was only expressed in CMT167 cells, not LLC cells, but neither of their viability was altered by IL-9 in vitro. However, IL-9 led to tumor suppression and facilitated intratumoral T lymphocyte immunity in IL-9R-positive CMT167 model, not in IL-9R-lacking LLC model. Upon IL-9R knockdown, IL-9 lost its efficacy to induce anticancer immunity and tumor inhibition in CMT167 model.
In CMT167 tumors, although IL-9 elevated both tumor-infiltrating CD4+ and CD8+ T lymphocytes, it was the cytotoxic T cell subset that mediated the tumor suppression by IL-9. To understand the mechanisms of IL-9-enhanced CD8+ T cell responses in CMT167 tumors, T cell activation markers, recruitment chemokines, dendritic cells (DCs) frequencies, and tumor cell-surface major histocompatibility complex (MHC)-I expression were investigated. Increased DCs and upregulated MHC-I were observed in CMT167 tumors upon IL-9 therapy, both of which were
III
absent in IL-9R knockdown CMT167 model. In vitro, IL-9 increased MHC-I expression in CMT167 and human lung adenocarcinoma A549 cells consistently. The signal transducer and activator of transcription 1 (STAT1) and protein kinase B (Akt) pathways in CMT167 cells were not affected, while phosphorylation of extracellular signal-regulated kinase (ERK) was enhanced by IL-9. The upregulation of MHC-I by IL-9 in CMT167 cells was abrogated by ERK inhibition.
Previously, others have reported a positive correlation of IL-9-producing T helper type 9 (Th9) cells with the therapeutic efficacy of PD-1 blockade in cancers, demonstrating that IL-9 and PD-1/PD-L1 inhibition might have a potential synergism. Indeed, besides the enhanced anti-tumor T cell immunity, IL-9 also increased the PD-1 expression on CD8+ T lymphocytes and PD-L1 expression on CMT167 cells. Combined treatment with IL-9 and PD-1 blockade further increased intratumoral cytotoxic T lymphocytes and synergistically inhibited the growth of CMT167 tumors.
In summary, IL-9/IL-9R interaction in CMT167 tumors could promote tumoral MHC-I presentation and increase DCs frequencies, leading to tumor growth suppression by enhanced cytotoxic T lymphocyte immunity. Intratumoral IL-9R expression might potentially be investigated as a selection biomarker for lung cancer subsets susceptible to IL-9 therapy. The findings from this study lend support
IV
for future clinical evaluation of IL-9 as an immunomodulatory agent in combination with PD-1 blockade in lung cancer. |
Degree | Doctor of Philosophy |
Subject | Lungs - Cancer - Animal models Interleukins |
Dept/Program | Medicine |
Persistent Identifier | http://hdl.handle.net/10722/327888 |
DC Field | Value | Language |
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dc.contributor.advisor | Ho, JCM | - |
dc.contributor.advisor | Mak, JCW | - |
dc.contributor.author | Feng, Yuqian | - |
dc.contributor.author | 馮玉倩 | - |
dc.date.accessioned | 2023-06-05T03:46:57Z | - |
dc.date.available | 2023-06-05T03:46:57Z | - |
dc.date.issued | 2023 | - |
dc.identifier.citation | Feng, Y. [馮玉倩]. (2023). The role and mechanisms of interleukin-9 in facilitating anticancer effect of immune checkpoint blockade in lung cancer animal model. (Thesis). University of Hong Kong, Pokfulam, Hong Kong SAR. | - |
dc.identifier.uri | http://hdl.handle.net/10722/327888 | - |
dc.description.abstract | Lung cancer remains the major reason for cancer-related deaths. Immune checkpoint blockade (ICB), particularly with the use of programmed cell death protein 1 (PD-1)/programmed cell death protein ligand 1 (PD-L1) antibodies, has gained major advancement in cancer therapy throughout the recent decade, nonetheless only a minority of patients may benefit. Therefore, novel immunotherapeutic targets and combination strategies are urgently needed to II expand the clinical benefit to wider patient population. Interleukin-9 (IL-9) is known to be important in modifying tumor biology and has pleiotropic effects in different cancers. In lung cancer, the function of IL-9 is not fully elucidated. The purpose of this study was to better understand the function(s) of IL-9 in lung cancer and the underlying mechanisms. Lewis lung carcinoma (LLC) and CMT167 murine lung cancer cell lines were utilized in this study. IL-9 receptor (IL-9R) was only expressed in CMT167 cells, not LLC cells, but neither of their viability was altered by IL-9 in vitro. However, IL-9 led to tumor suppression and facilitated intratumoral T lymphocyte immunity in IL-9R-positive CMT167 model, not in IL-9R-lacking LLC model. Upon IL-9R knockdown, IL-9 lost its efficacy to induce anticancer immunity and tumor inhibition in CMT167 model. In CMT167 tumors, although IL-9 elevated both tumor-infiltrating CD4+ and CD8+ T lymphocytes, it was the cytotoxic T cell subset that mediated the tumor suppression by IL-9. To understand the mechanisms of IL-9-enhanced CD8+ T cell responses in CMT167 tumors, T cell activation markers, recruitment chemokines, dendritic cells (DCs) frequencies, and tumor cell-surface major histocompatibility complex (MHC)-I expression were investigated. Increased DCs and upregulated MHC-I were observed in CMT167 tumors upon IL-9 therapy, both of which were III absent in IL-9R knockdown CMT167 model. In vitro, IL-9 increased MHC-I expression in CMT167 and human lung adenocarcinoma A549 cells consistently. The signal transducer and activator of transcription 1 (STAT1) and protein kinase B (Akt) pathways in CMT167 cells were not affected, while phosphorylation of extracellular signal-regulated kinase (ERK) was enhanced by IL-9. The upregulation of MHC-I by IL-9 in CMT167 cells was abrogated by ERK inhibition. Previously, others have reported a positive correlation of IL-9-producing T helper type 9 (Th9) cells with the therapeutic efficacy of PD-1 blockade in cancers, demonstrating that IL-9 and PD-1/PD-L1 inhibition might have a potential synergism. Indeed, besides the enhanced anti-tumor T cell immunity, IL-9 also increased the PD-1 expression on CD8+ T lymphocytes and PD-L1 expression on CMT167 cells. Combined treatment with IL-9 and PD-1 blockade further increased intratumoral cytotoxic T lymphocytes and synergistically inhibited the growth of CMT167 tumors. In summary, IL-9/IL-9R interaction in CMT167 tumors could promote tumoral MHC-I presentation and increase DCs frequencies, leading to tumor growth suppression by enhanced cytotoxic T lymphocyte immunity. Intratumoral IL-9R expression might potentially be investigated as a selection biomarker for lung cancer subsets susceptible to IL-9 therapy. The findings from this study lend support IV for future clinical evaluation of IL-9 as an immunomodulatory agent in combination with PD-1 blockade in lung cancer. | - |
dc.language | eng | - |
dc.publisher | The University of Hong Kong (Pokfulam, Hong Kong) | - |
dc.relation.ispartof | HKU Theses Online (HKUTO) | - |
dc.rights | The author retains all proprietary rights, (such as patent rights) and the right to use in future works. | - |
dc.rights | This work is licensed under a Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International License. | - |
dc.subject.lcsh | Lungs - Cancer - Animal models | - |
dc.subject.lcsh | Interleukins | - |
dc.title | The role and mechanisms of interleukin-9 in facilitating anticancer effect of immune checkpoint blockade in lung cancer animal model | - |
dc.type | PG_Thesis | - |
dc.description.thesisname | Doctor of Philosophy | - |
dc.description.thesislevel | Doctoral | - |
dc.description.thesisdiscipline | Medicine | - |
dc.description.nature | published_or_final_version | - |
dc.date.hkucongregation | 2023 | - |
dc.identifier.mmsid | 991044683800503414 | - |