Engineered GM-CSF polarizes protumorigenic tumor-associated macrophages to an antitumorigenic phenotype and potently synergizes with IL-12 immunotherapy
Background The use of immune checkpoint inhibitors (CPIs) has become a dominant regimen in modern cancer therapy, however immune resistance induced by tumor-associated macrophages (TAMs) with immune suppressive and evasion properties limits responses. Therefore, the rational design of immune modulat...
Saved in:
| Main Authors: | , , , , , , , , , , , , , , , , , , , , |
|---|---|
| Format: | Article |
| Language: | English |
| Published: |
BMJ Publishing Group
2024-12-01
|
| Series: | Journal for ImmunoTherapy of Cancer |
| Online Access: | https://jitc.bmj.com/content/12/12/e009541.full |
| Tags: |
Add Tag
No Tags, Be the first to tag this record!
|
| _version_ | 1841536285920985088 |
|---|---|
| author | Yue Wang Kevin Chang Aslan Mansurov Jun Ishihara Seounghun Kang Trevin Kurtanich Hye Rin Chun Anna J Slezak Lisa R Volpatti Thomas Wang Aaron T Alpar Kirsten C Refvik O Isabella Hansen Gustavo J Borjas Brendan T K Berg Ha-Na Shim Kevin T Hultgren Suzana Gomes Ani Solanki Melody A Swartz Jeffrey A Hubbell |
| author_facet | Yue Wang Kevin Chang Aslan Mansurov Jun Ishihara Seounghun Kang Trevin Kurtanich Hye Rin Chun Anna J Slezak Lisa R Volpatti Thomas Wang Aaron T Alpar Kirsten C Refvik O Isabella Hansen Gustavo J Borjas Brendan T K Berg Ha-Na Shim Kevin T Hultgren Suzana Gomes Ani Solanki Melody A Swartz Jeffrey A Hubbell |
| author_sort | Yue Wang |
| collection | DOAJ |
| description | Background The use of immune checkpoint inhibitors (CPIs) has become a dominant regimen in modern cancer therapy, however immune resistance induced by tumor-associated macrophages (TAMs) with immune suppressive and evasion properties limits responses. Therefore, the rational design of immune modulators that can control the immune suppressive properties of TAMs and polarize them, as well as dendritic cells (DCs), toward a more proinflammatory phenotype is a principal objective in cancer immunotherapy.Methods Here, using a protein engineering approach to enhance cytokine residence in the tumor microenvironment, we examined combined stimulation of the myeloid compartment via tumor stroma-binding granulocyte–macrophage colony-stimulating factor (GM-CSF) to enhance responses in both DCs and T cells via stroma-binding interleukin-12 (IL-12). We evaluated tumor responses at the levels of outcome, cellular responses, and cytokine responses in both the tumors and the tumor-draining lymph nodes. We further investigated the potentiation of DC response to IL-12 by GM-CSF stimulation ex vivo.Results Engineered GM-CSF restored an antitumorigenic tumor myeloid microenvironment otherwise suppressed by TAMs, while engineered IL-12 provided effector signals to T cells, thereby boosting both tumor-resident antitumor macrophage and CD8+ T cell populations. Furthermore, engineered GM-CSF potentiated DC response to IL-12, upregulating DC expression of IL-12 receptor and enhancing their expression of proinflammatory cytokines and chemokines on IL-12 exposure. This resulted in remarkable synergistic efficacy in multiple solid tumor models treated with the dual cytokine combination. The combination therapy also improved the efficacy of CPI in a CPI-resistant genetically-engineered melanoma model and exhibited synergistic antitumor efficacy in a pulmonary metastasis model.Conclusion Our strategy provides a rational design for combination immunotherapy targeting both myeloid and lymphoid compartments through complementary mechanisms. |
| format | Article |
| id | doaj-art-c8bb8c47c7c94894ab8b085ac5129c0d |
| institution | Kabale University |
| issn | 2051-1426 |
| language | English |
| publishDate | 2024-12-01 |
| publisher | BMJ Publishing Group |
| record_format | Article |
| series | Journal for ImmunoTherapy of Cancer |
| spelling | doaj-art-c8bb8c47c7c94894ab8b085ac5129c0d2025-01-14T20:50:09ZengBMJ Publishing GroupJournal for ImmunoTherapy of Cancer2051-14262024-12-01121210.1136/jitc-2024-009541Engineered GM-CSF polarizes protumorigenic tumor-associated macrophages to an antitumorigenic phenotype and potently synergizes with IL-12 immunotherapyYue Wang0Kevin Chang1Aslan Mansurov2Jun Ishihara3Seounghun Kang4Trevin Kurtanich5Hye Rin Chun6Anna J Slezak7Lisa R Volpatti8Thomas Wang9Aaron T Alpar10Kirsten C Refvik11O Isabella Hansen12Gustavo J Borjas13Brendan T K Berg14Ha-Na Shim15Kevin T Hultgren16Suzana Gomes17Ani Solanki18Melody A Swartz19Jeffrey A Hubbell20Pritzker School of Molecular Engineering, The University of Chicago, Chicago, Illinois, USAPritzker School of Molecular Engineering, The University of Chicago, Chicago, Illinois, USAPritzker School of Molecular Engineering, The University of Chicago, Chicago, Illinois, USADepartment of Bioengineering, Imperial College London, London, UKPritzker School of Molecular Engineering, The University of Chicago, Chicago, Illinois, USAPritzker School of Molecular Engineering, The University of Chicago, Chicago, Illinois, USACommittee on Immunology, The University of Chicago, Chicago, Illinois, USAPritzker School of Molecular Engineering, The University of Chicago, Chicago, Illinois, USAPritzker School of Molecular Engineering, The University of Chicago, Chicago, Illinois, USAPritzker School of Molecular Engineering, The University of Chicago, Chicago, Illinois, USAPritzker School of Molecular Engineering, The University of Chicago, Chicago, Illinois, USAPritzker School of Molecular Engineering, The University of Chicago, Chicago, Illinois, USAPritzker School of Molecular Engineering, The University of Chicago, Chicago, Illinois, USAPritzker School of Molecular Engineering, The University of Chicago, Chicago, Illinois, USAPritzker School of Molecular Engineering, The University of Chicago, Chicago, Illinois, USAPritzker School of Molecular Engineering, The University of Chicago, Chicago, Illinois, USAPritzker School of Molecular Engineering, The University of Chicago, Chicago, Illinois, USAPritzker School of Molecular Engineering, The University of Chicago, Chicago, Illinois, USAAnimal Resource Center, The University of Chicago, Chicago, Illinois, USAPritzker School of Molecular Engineering, The University of Chicago, Chicago, Illinois, USAPritzker School of Molecular Engineering, The University of Chicago, Chicago, Illinois, USABackground The use of immune checkpoint inhibitors (CPIs) has become a dominant regimen in modern cancer therapy, however immune resistance induced by tumor-associated macrophages (TAMs) with immune suppressive and evasion properties limits responses. Therefore, the rational design of immune modulators that can control the immune suppressive properties of TAMs and polarize them, as well as dendritic cells (DCs), toward a more proinflammatory phenotype is a principal objective in cancer immunotherapy.Methods Here, using a protein engineering approach to enhance cytokine residence in the tumor microenvironment, we examined combined stimulation of the myeloid compartment via tumor stroma-binding granulocyte–macrophage colony-stimulating factor (GM-CSF) to enhance responses in both DCs and T cells via stroma-binding interleukin-12 (IL-12). We evaluated tumor responses at the levels of outcome, cellular responses, and cytokine responses in both the tumors and the tumor-draining lymph nodes. We further investigated the potentiation of DC response to IL-12 by GM-CSF stimulation ex vivo.Results Engineered GM-CSF restored an antitumorigenic tumor myeloid microenvironment otherwise suppressed by TAMs, while engineered IL-12 provided effector signals to T cells, thereby boosting both tumor-resident antitumor macrophage and CD8+ T cell populations. Furthermore, engineered GM-CSF potentiated DC response to IL-12, upregulating DC expression of IL-12 receptor and enhancing their expression of proinflammatory cytokines and chemokines on IL-12 exposure. This resulted in remarkable synergistic efficacy in multiple solid tumor models treated with the dual cytokine combination. The combination therapy also improved the efficacy of CPI in a CPI-resistant genetically-engineered melanoma model and exhibited synergistic antitumor efficacy in a pulmonary metastasis model.Conclusion Our strategy provides a rational design for combination immunotherapy targeting both myeloid and lymphoid compartments through complementary mechanisms.https://jitc.bmj.com/content/12/12/e009541.full |
| spellingShingle | Yue Wang Kevin Chang Aslan Mansurov Jun Ishihara Seounghun Kang Trevin Kurtanich Hye Rin Chun Anna J Slezak Lisa R Volpatti Thomas Wang Aaron T Alpar Kirsten C Refvik O Isabella Hansen Gustavo J Borjas Brendan T K Berg Ha-Na Shim Kevin T Hultgren Suzana Gomes Ani Solanki Melody A Swartz Jeffrey A Hubbell Engineered GM-CSF polarizes protumorigenic tumor-associated macrophages to an antitumorigenic phenotype and potently synergizes with IL-12 immunotherapy Journal for ImmunoTherapy of Cancer |
| title | Engineered GM-CSF polarizes protumorigenic tumor-associated macrophages to an antitumorigenic phenotype and potently synergizes with IL-12 immunotherapy |
| title_full | Engineered GM-CSF polarizes protumorigenic tumor-associated macrophages to an antitumorigenic phenotype and potently synergizes with IL-12 immunotherapy |
| title_fullStr | Engineered GM-CSF polarizes protumorigenic tumor-associated macrophages to an antitumorigenic phenotype and potently synergizes with IL-12 immunotherapy |
| title_full_unstemmed | Engineered GM-CSF polarizes protumorigenic tumor-associated macrophages to an antitumorigenic phenotype and potently synergizes with IL-12 immunotherapy |
| title_short | Engineered GM-CSF polarizes protumorigenic tumor-associated macrophages to an antitumorigenic phenotype and potently synergizes with IL-12 immunotherapy |
| title_sort | engineered gm csf polarizes protumorigenic tumor associated macrophages to an antitumorigenic phenotype and potently synergizes with il 12 immunotherapy |
| url | https://jitc.bmj.com/content/12/12/e009541.full |
| work_keys_str_mv | AT yuewang engineeredgmcsfpolarizesprotumorigenictumorassociatedmacrophagestoanantitumorigenicphenotypeandpotentlysynergizeswithil12immunotherapy AT kevinchang engineeredgmcsfpolarizesprotumorigenictumorassociatedmacrophagestoanantitumorigenicphenotypeandpotentlysynergizeswithil12immunotherapy AT aslanmansurov engineeredgmcsfpolarizesprotumorigenictumorassociatedmacrophagestoanantitumorigenicphenotypeandpotentlysynergizeswithil12immunotherapy AT junishihara engineeredgmcsfpolarizesprotumorigenictumorassociatedmacrophagestoanantitumorigenicphenotypeandpotentlysynergizeswithil12immunotherapy AT seounghunkang engineeredgmcsfpolarizesprotumorigenictumorassociatedmacrophagestoanantitumorigenicphenotypeandpotentlysynergizeswithil12immunotherapy AT trevinkurtanich engineeredgmcsfpolarizesprotumorigenictumorassociatedmacrophagestoanantitumorigenicphenotypeandpotentlysynergizeswithil12immunotherapy AT hyerinchun engineeredgmcsfpolarizesprotumorigenictumorassociatedmacrophagestoanantitumorigenicphenotypeandpotentlysynergizeswithil12immunotherapy AT annajslezak engineeredgmcsfpolarizesprotumorigenictumorassociatedmacrophagestoanantitumorigenicphenotypeandpotentlysynergizeswithil12immunotherapy AT lisarvolpatti engineeredgmcsfpolarizesprotumorigenictumorassociatedmacrophagestoanantitumorigenicphenotypeandpotentlysynergizeswithil12immunotherapy AT thomaswang engineeredgmcsfpolarizesprotumorigenictumorassociatedmacrophagestoanantitumorigenicphenotypeandpotentlysynergizeswithil12immunotherapy AT aarontalpar engineeredgmcsfpolarizesprotumorigenictumorassociatedmacrophagestoanantitumorigenicphenotypeandpotentlysynergizeswithil12immunotherapy AT kirstencrefvik engineeredgmcsfpolarizesprotumorigenictumorassociatedmacrophagestoanantitumorigenicphenotypeandpotentlysynergizeswithil12immunotherapy AT oisabellahansen engineeredgmcsfpolarizesprotumorigenictumorassociatedmacrophagestoanantitumorigenicphenotypeandpotentlysynergizeswithil12immunotherapy AT gustavojborjas engineeredgmcsfpolarizesprotumorigenictumorassociatedmacrophagestoanantitumorigenicphenotypeandpotentlysynergizeswithil12immunotherapy AT brendantkberg engineeredgmcsfpolarizesprotumorigenictumorassociatedmacrophagestoanantitumorigenicphenotypeandpotentlysynergizeswithil12immunotherapy AT hanashim engineeredgmcsfpolarizesprotumorigenictumorassociatedmacrophagestoanantitumorigenicphenotypeandpotentlysynergizeswithil12immunotherapy AT kevinthultgren engineeredgmcsfpolarizesprotumorigenictumorassociatedmacrophagestoanantitumorigenicphenotypeandpotentlysynergizeswithil12immunotherapy AT suzanagomes engineeredgmcsfpolarizesprotumorigenictumorassociatedmacrophagestoanantitumorigenicphenotypeandpotentlysynergizeswithil12immunotherapy AT anisolanki engineeredgmcsfpolarizesprotumorigenictumorassociatedmacrophagestoanantitumorigenicphenotypeandpotentlysynergizeswithil12immunotherapy AT melodyaswartz engineeredgmcsfpolarizesprotumorigenictumorassociatedmacrophagestoanantitumorigenicphenotypeandpotentlysynergizeswithil12immunotherapy AT jeffreyahubbell engineeredgmcsfpolarizesprotumorigenictumorassociatedmacrophagestoanantitumorigenicphenotypeandpotentlysynergizeswithil12immunotherapy |