The CD40 agonist HERA-CD40L results in enhanced activation of antigen presenting cells, promoting an anti-tumor effect alone and in combination with radiotherapy
IntroductionThe ability to modulate and enhance the anti-tumor immune responses is critical in developing novel therapies in cancer. The Tumor Necrosis Factor (TNF) Receptor Super Family (TNFRSF) are potentially excellent targets for modulation which result in specific anti-tumor immune responses. C...
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| Format: | Article |
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Frontiers Media S.A.
2023-05-01
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| Series: | Frontiers in Immunology |
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| Online Access: | https://www.frontiersin.org/articles/10.3389/fimmu.2023.1160116/full |
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| author | Jamie Frankish Debayan Mukherjee Erminia Romano Katharina Billian-Frey Matthias Schröder Karl Heinonen Christian Merz Mauricio Redondo Müller Christian Gieffers Oliver Hill Meinolf Thiemann Jamie Honeychurch Tim Illidge Jaromir Sykora |
| author_facet | Jamie Frankish Debayan Mukherjee Erminia Romano Katharina Billian-Frey Matthias Schröder Karl Heinonen Christian Merz Mauricio Redondo Müller Christian Gieffers Oliver Hill Meinolf Thiemann Jamie Honeychurch Tim Illidge Jaromir Sykora |
| author_sort | Jamie Frankish |
| collection | DOAJ |
| description | IntroductionThe ability to modulate and enhance the anti-tumor immune responses is critical in developing novel therapies in cancer. The Tumor Necrosis Factor (TNF) Receptor Super Family (TNFRSF) are potentially excellent targets for modulation which result in specific anti-tumor immune responses. CD40 is a member of the TNFRSF and several clinical therapies are under development. CD40 signaling plays a pivotal role in regulating the immune system from B cell responses to myeloid cell driven activation of T cells. The CD40 signaling axis is well characterized and here we compare next generation HERA-Ligands to conventional monoclonal antibody based immune modulation for the treatment of cancer.Methods & resultsHERA-CD40L is a novel molecule that targets CD40 mediated signal transduction and demonstrates a clear mode of action in generating an activated receptor complex via recruitment of TRAFs, cIAP1, and HOIP, leading to TRAF2 phosphorylation and ultimately resulting in the enhanced activation of key inflammatory/survival pathway and transcription factors such asNFkB, AKT, p38, ERK1/2, JNK, and STAT1 in dendritic cells. Furthermore, HERA-CD40L demonstrated a strong modulation of the tumor microenvironment (TME) via the increase in intratumoral CD8+ T cells and the functional switch from pro-tumor macrophages (TAMs) to anti-tumor macrophages that together results in a significant reduction of tumor growth in a CT26 mouse model. Furthermore, radiotherapy which may have an immunosuppressive modulation of the TME, was shown to have an immunostimulatory effect in combination with HERA-CD40L. Radiotherapy in combination with HERA-CD40L treatment resulted in an increase in detected intratumoral CD4+/8+ T cells compared to RT alone and, additionally, the repolarization of TAMs was also observed, resulting in an inhibition of tumor growth in a TRAMP-C1 mouse model.DiscussionTaken together, HERA-CD40L resulted in activating signal transduction mechanisms in dendritic cells, resulting in an increase in intratumoral T cells and manipulation of the TME to be pro-inflammatory, repolarizing M2 macrophages to M1, enhancing tumor control. |
| first_indexed | 2024-03-13T09:27:00Z |
| format | Article |
| id | doaj.art-3a2c8f98856e4fc4a7c38804f359c93f |
| institution | Directory Open Access Journal |
| issn | 1664-3224 |
| language | English |
| last_indexed | 2024-03-13T09:27:00Z |
| publishDate | 2023-05-01 |
| publisher | Frontiers Media S.A. |
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| series | Frontiers in Immunology |
| spelling | doaj.art-3a2c8f98856e4fc4a7c38804f359c93f2023-05-26T08:56:33ZengFrontiers Media S.A.Frontiers in Immunology1664-32242023-05-011410.3389/fimmu.2023.11601161160116The CD40 agonist HERA-CD40L results in enhanced activation of antigen presenting cells, promoting an anti-tumor effect alone and in combination with radiotherapyJamie Frankish0Debayan Mukherjee1Erminia Romano2Katharina Billian-Frey3Matthias Schröder4Karl Heinonen5Christian Merz6Mauricio Redondo Müller7Christian Gieffers8Oliver Hill9Meinolf Thiemann10Jamie Honeychurch11Tim Illidge12Jaromir Sykora13Apogenix AG, Heidelberg, GermanyTargeted Therapy Group, Division of Cancer Sciences, Faculty of Biology Medicine and Health, The University of Manchester, Manchester, United KingdomTargeted Therapy Group, Division of Cancer Sciences, Faculty of Biology Medicine and Health, The University of Manchester, Manchester, United KingdomApogenix AG, Heidelberg, GermanyApogenix AG, Heidelberg, GermanyApogenix AG, Heidelberg, GermanyApogenix AG, Heidelberg, GermanyApogenix AG, Heidelberg, GermanyApogenix AG, Heidelberg, GermanyApogenix AG, Heidelberg, GermanyApogenix AG, Heidelberg, GermanyTargeted Therapy Group, Division of Cancer Sciences, Faculty of Biology Medicine and Health, The University of Manchester, Manchester, United KingdomTargeted Therapy Group, Division of Cancer Sciences, Faculty of Biology Medicine and Health, The University of Manchester, Manchester, United KingdomApogenix AG, Heidelberg, GermanyIntroductionThe ability to modulate and enhance the anti-tumor immune responses is critical in developing novel therapies in cancer. The Tumor Necrosis Factor (TNF) Receptor Super Family (TNFRSF) are potentially excellent targets for modulation which result in specific anti-tumor immune responses. CD40 is a member of the TNFRSF and several clinical therapies are under development. CD40 signaling plays a pivotal role in regulating the immune system from B cell responses to myeloid cell driven activation of T cells. The CD40 signaling axis is well characterized and here we compare next generation HERA-Ligands to conventional monoclonal antibody based immune modulation for the treatment of cancer.Methods & resultsHERA-CD40L is a novel molecule that targets CD40 mediated signal transduction and demonstrates a clear mode of action in generating an activated receptor complex via recruitment of TRAFs, cIAP1, and HOIP, leading to TRAF2 phosphorylation and ultimately resulting in the enhanced activation of key inflammatory/survival pathway and transcription factors such asNFkB, AKT, p38, ERK1/2, JNK, and STAT1 in dendritic cells. Furthermore, HERA-CD40L demonstrated a strong modulation of the tumor microenvironment (TME) via the increase in intratumoral CD8+ T cells and the functional switch from pro-tumor macrophages (TAMs) to anti-tumor macrophages that together results in a significant reduction of tumor growth in a CT26 mouse model. Furthermore, radiotherapy which may have an immunosuppressive modulation of the TME, was shown to have an immunostimulatory effect in combination with HERA-CD40L. Radiotherapy in combination with HERA-CD40L treatment resulted in an increase in detected intratumoral CD4+/8+ T cells compared to RT alone and, additionally, the repolarization of TAMs was also observed, resulting in an inhibition of tumor growth in a TRAMP-C1 mouse model.DiscussionTaken together, HERA-CD40L resulted in activating signal transduction mechanisms in dendritic cells, resulting in an increase in intratumoral T cells and manipulation of the TME to be pro-inflammatory, repolarizing M2 macrophages to M1, enhancing tumor control.https://www.frontiersin.org/articles/10.3389/fimmu.2023.1160116/fullCD40HERA-CD40LTNFRSFTRAF2tumor micro environment (TME)antigen presenting cells |
| spellingShingle | Jamie Frankish Debayan Mukherjee Erminia Romano Katharina Billian-Frey Matthias Schröder Karl Heinonen Christian Merz Mauricio Redondo Müller Christian Gieffers Oliver Hill Meinolf Thiemann Jamie Honeychurch Tim Illidge Jaromir Sykora The CD40 agonist HERA-CD40L results in enhanced activation of antigen presenting cells, promoting an anti-tumor effect alone and in combination with radiotherapy Frontiers in Immunology CD40 HERA-CD40L TNFRSF TRAF2 tumor micro environment (TME) antigen presenting cells |
| title | The CD40 agonist HERA-CD40L results in enhanced activation of antigen presenting cells, promoting an anti-tumor effect alone and in combination with radiotherapy |
| title_full | The CD40 agonist HERA-CD40L results in enhanced activation of antigen presenting cells, promoting an anti-tumor effect alone and in combination with radiotherapy |
| title_fullStr | The CD40 agonist HERA-CD40L results in enhanced activation of antigen presenting cells, promoting an anti-tumor effect alone and in combination with radiotherapy |
| title_full_unstemmed | The CD40 agonist HERA-CD40L results in enhanced activation of antigen presenting cells, promoting an anti-tumor effect alone and in combination with radiotherapy |
| title_short | The CD40 agonist HERA-CD40L results in enhanced activation of antigen presenting cells, promoting an anti-tumor effect alone and in combination with radiotherapy |
| title_sort | cd40 agonist hera cd40l results in enhanced activation of antigen presenting cells promoting an anti tumor effect alone and in combination with radiotherapy |
| topic | CD40 HERA-CD40L TNFRSF TRAF2 tumor micro environment (TME) antigen presenting cells |
| url | https://www.frontiersin.org/articles/10.3389/fimmu.2023.1160116/full |
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