Arginase-1-specific T cells target and modulate tumor-associated macrophages
Background Arginase-1 (Arg1) expressing tumor-associated macrophages (TAMs) may create an immune-suppressive tumor microenvironment (TME), which is a significant challenge for cancer immunotherapy. We previously reported the existence of Arg1-specific memory T cells among peripheral blood mononuclea...
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| Format: | Article |
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BMJ Publishing Group
2025-01-01
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| Series: | Journal for ImmunoTherapy of Cancer |
| Online Access: | https://jitc.bmj.com/content/13/1/e009930.full |
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| author | Mads Hald Andersen Inés Lecoq Ayako Wakatsuki Pedersen Evelina Martinenaite Shamaila Munir Ahmad Maria Perez-Penco Lucia Lara de la Torre Marion Chapellier Lars Rønn Olsen Mia Aaboe-Jørgensen Hannah Jorinde Glöckner Anne Mette Askehøj Rømer |
| author_facet | Mads Hald Andersen Inés Lecoq Ayako Wakatsuki Pedersen Evelina Martinenaite Shamaila Munir Ahmad Maria Perez-Penco Lucia Lara de la Torre Marion Chapellier Lars Rønn Olsen Mia Aaboe-Jørgensen Hannah Jorinde Glöckner Anne Mette Askehøj Rømer |
| author_sort | Mads Hald Andersen |
| collection | DOAJ |
| description | Background Arginase-1 (Arg1) expressing tumor-associated macrophages (TAMs) may create an immune-suppressive tumor microenvironment (TME), which is a significant challenge for cancer immunotherapy. We previously reported the existence of Arg1-specific memory T cells among peripheral blood mononuclear cells (PBMCs) and described that Arg-1-based immune modulatory vaccines (IMVs) control tumor growth and alter the M1/M2 macrophage ratio in murine models of cancer. In the present study, we investigated how Arg1-specific T cells can directly target TAMs and influence their polarization.Methods Murine Arg1-specific CD4+T cells isolated from splenocytes of animals vaccinated with an Arg1-derived peptide in the adjuvant montanide were co-cultured with either in vitro M2-differentiated bone marrow-derived macrophages or ex vivo isolated F4/80+TAMs. Human Arg1-specific CD4+T cell clones were co-cultured with Arg1-expressing TAMs generated in vitro from either PBMC-derived CD14+cells or the myeloid cell lines MonoMac1 and THP-1. MHC class II-restricted Arg-1 peptide presentation by macrophages was confirmed by immunopeptidomics. T-cell-mediated changes in the macrophage immune phenotype and cytokine microenvironment were examined using flow cytometry, RT-qPCR and multiplex immunoassay. The effect of Arg1-derived peptide IMV on TAMs in vivo was assessed by multiplex gene analysis of F4/80+cells.Results We show that Arg1-based IMV-mediated tumor control was linked to a decrease in multiple immunosuppressive pathways in the TAM population of the treated animals. Tumor-conditioned media (TCM) derived from Arg1-vaccinated mice induced significantly higher upregulation of MHC-II on exposed myeloid cells compared with controls. Furthermore, murine CD4+Arg1-specific T cells were able to target TAMs and effectively reprogram their phenotype ex vivo by secreting IL2 and IFNγ. Next, we established that human Arg1+TAMs present Arg1-derived peptides and are directly recognized by proinflammatory CD4+Arg1-specific T cell clones. These CD4+Arg1-specific T cells were able to reprogram TCM-conditioned macrophages as observed by increased expression of CD80 and HLA-DR.Conclusions TAMs may be directly targeted and modulated by Arg1-specific CD4+T cells. These findings provide a strong rationale for future clinical development of Arg1-based IMVs to alter the immune-suppressive TME by reprogramming TAMs and promoting a proinflammatory TME. |
| format | Article |
| id | doaj-art-c3bbd3c09af54c46bbbac8253cd7298b |
| institution | Kabale University |
| issn | 2051-1426 |
| language | English |
| publishDate | 2025-01-01 |
| publisher | BMJ Publishing Group |
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| series | Journal for ImmunoTherapy of Cancer |
| spelling | doaj-art-c3bbd3c09af54c46bbbac8253cd7298b2025-01-31T20:50:09ZengBMJ Publishing GroupJournal for ImmunoTherapy of Cancer2051-14262025-01-0113110.1136/jitc-2024-009930Arginase-1-specific T cells target and modulate tumor-associated macrophagesMads Hald Andersen0Inés Lecoq1Ayako Wakatsuki Pedersen2Evelina Martinenaite3Shamaila Munir Ahmad4Maria Perez-Penco5Lucia Lara de la Torre6Marion Chapellier7Lars Rønn Olsen8Mia Aaboe-Jørgensen9Hannah Jorinde Glöckner10Anne Mette Askehøj Rømer11National Center for Cancer Immune Therapy (CCIT-DK), Department of Oncology, Herlev Hospital, Herlev, DenmarkNational Center for Cancer Immune Therapy (CCIT-DK), Department of Oncology, Herlev Hospital, Herlev, DenmarkIO Biotech ApS, Copenhagen, DenmarkNational Center for Cancer Immune Therapy (CCIT-DK), Department of Oncology, Herlev Hospital, Herlev, DenmarkNational Center for Cancer Immune Therapy (CCIT-DK), Department of Oncology, Herlev Hospital, Herlev, DenmarkNational Center for Cancer Immune Therapy (CCIT-DK), Department of Oncology, Herlev Hospital, Herlev, DenmarkNational Center for Cancer Immune Therapy (CCIT-DK), Department of Oncology, Herlev Hospital, Herlev, DenmarkIO Biotech ApS, Copenhagen, DenmarkSection for Bioinformatics, Department of Health Technology, Technical University of Denmark, Lyngby, DenmarkNational Center for Cancer Immune Therapy (CCIT-DK), Department of Oncology, Herlev Hospital, Herlev, DenmarkNational Center for Cancer Immune Therapy (CCIT-DK), Department of Oncology, Herlev Hospital, Herlev, DenmarkNational Center for Cancer Immune Therapy (CCIT-DK), Department of Oncology, Herlev Hospital, Herlev, DenmarkBackground Arginase-1 (Arg1) expressing tumor-associated macrophages (TAMs) may create an immune-suppressive tumor microenvironment (TME), which is a significant challenge for cancer immunotherapy. We previously reported the existence of Arg1-specific memory T cells among peripheral blood mononuclear cells (PBMCs) and described that Arg-1-based immune modulatory vaccines (IMVs) control tumor growth and alter the M1/M2 macrophage ratio in murine models of cancer. In the present study, we investigated how Arg1-specific T cells can directly target TAMs and influence their polarization.Methods Murine Arg1-specific CD4+T cells isolated from splenocytes of animals vaccinated with an Arg1-derived peptide in the adjuvant montanide were co-cultured with either in vitro M2-differentiated bone marrow-derived macrophages or ex vivo isolated F4/80+TAMs. Human Arg1-specific CD4+T cell clones were co-cultured with Arg1-expressing TAMs generated in vitro from either PBMC-derived CD14+cells or the myeloid cell lines MonoMac1 and THP-1. MHC class II-restricted Arg-1 peptide presentation by macrophages was confirmed by immunopeptidomics. T-cell-mediated changes in the macrophage immune phenotype and cytokine microenvironment were examined using flow cytometry, RT-qPCR and multiplex immunoassay. The effect of Arg1-derived peptide IMV on TAMs in vivo was assessed by multiplex gene analysis of F4/80+cells.Results We show that Arg1-based IMV-mediated tumor control was linked to a decrease in multiple immunosuppressive pathways in the TAM population of the treated animals. Tumor-conditioned media (TCM) derived from Arg1-vaccinated mice induced significantly higher upregulation of MHC-II on exposed myeloid cells compared with controls. Furthermore, murine CD4+Arg1-specific T cells were able to target TAMs and effectively reprogram their phenotype ex vivo by secreting IL2 and IFNγ. Next, we established that human Arg1+TAMs present Arg1-derived peptides and are directly recognized by proinflammatory CD4+Arg1-specific T cell clones. These CD4+Arg1-specific T cells were able to reprogram TCM-conditioned macrophages as observed by increased expression of CD80 and HLA-DR.Conclusions TAMs may be directly targeted and modulated by Arg1-specific CD4+T cells. These findings provide a strong rationale for future clinical development of Arg1-based IMVs to alter the immune-suppressive TME by reprogramming TAMs and promoting a proinflammatory TME.https://jitc.bmj.com/content/13/1/e009930.full |
| spellingShingle | Mads Hald Andersen Inés Lecoq Ayako Wakatsuki Pedersen Evelina Martinenaite Shamaila Munir Ahmad Maria Perez-Penco Lucia Lara de la Torre Marion Chapellier Lars Rønn Olsen Mia Aaboe-Jørgensen Hannah Jorinde Glöckner Anne Mette Askehøj Rømer Arginase-1-specific T cells target and modulate tumor-associated macrophages Journal for ImmunoTherapy of Cancer |
| title | Arginase-1-specific T cells target and modulate tumor-associated macrophages |
| title_full | Arginase-1-specific T cells target and modulate tumor-associated macrophages |
| title_fullStr | Arginase-1-specific T cells target and modulate tumor-associated macrophages |
| title_full_unstemmed | Arginase-1-specific T cells target and modulate tumor-associated macrophages |
| title_short | Arginase-1-specific T cells target and modulate tumor-associated macrophages |
| title_sort | arginase 1 specific t cells target and modulate tumor associated macrophages |
| url | https://jitc.bmj.com/content/13/1/e009930.full |
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