FAP-CD40 and PD1-IL2v combination therapy reprograms immunologically cold tumors through de novo intratumoral T cell-dendritic cell clusters
Background Pancreatic ductal adenocarcinoma (PDAC) remains a major challenge for immunotherapy due to its immunologically cold tumor nature, characterized by poor T cell infiltration and a highly suppressive tumor microenvironment. Here, we propose a novel strategy, combining fibroblast activation p...
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| Main Authors: | , , , , , , , , , , , , |
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| Format: | Article (Journal) |
| Language: | English |
| Published: |
May 2026
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| In: |
Journal for ImmunoTherapy of Cancer
Year: 2026, Volume: 14, Issue: 5, Pages: 1-20 |
| ISSN: | 2051-1426 |
| DOI: | 10.1136/jitc-2025-014620 |
| Online Access: | Verlag, kostenfrei, Volltext: https://doi.org/10.1136/jitc-2025-014620 Verlag, kostenfrei, Volltext: https://jitc.bmj.com/content/14/5/e014620 
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| Author Notes: | Thuy Trinh Nguyen, Harold Gómez, Mechthild Lutge, Emilio Yángüez, Tamara Hüsser, Sina Nassiri, Christine Trumpfheller, Sara Colombetti, Laura Codarri Deak, Pablo Umaña, Sònia Tugues, Ines Grazina de Matos, Leo Kunz |
| Summary: | Background Pancreatic ductal adenocarcinoma (PDAC) remains a major challenge for immunotherapy due to its immunologically cold tumor nature, characterized by poor T cell infiltration and a highly suppressive tumor microenvironment. Here, we propose a novel strategy, combining fibroblast activation protein (FAP)-CD40 to activate dendritic cells (DCs) in the tumor microenvironment and programmed cell death protein-1 (PD1)-interleukin 2v (IL2v) to promote the expansion and differentiation of tumor-infiltrating T cells. We hypothesize that this combination will synergistically enhance both T cell priming and expansion directly within pancreatic 4662 KPC tumors, which recapitulate the immunologically cold features of human PDAC.Methods Immune cell distribution and abundance following FAP-CD40/PD1-IL2v monotherapy or combination therapy were analyzed using multiplexed confocal imaging (3D immune phenotyping). FTY720 studies assessed the contribution of lymph node priming in treatment efficacy, while CD4+/CD8+ T cell depletion experiments identified the roles of these subsets in combination therapy. T cell functionality was further assessed through ex vivo restimulation assays and single-cell RNA sequencing.Results Combination therapy induced dense intratumoral clusters of CD4 + and CD8+ T cells, colocalized with type 1 conventional DCs, termed as T cell-DC clusters (TDCs). These TDCs were strongly associated with tumor regression, which required both CD4+ and CD8+ T cells. Furthermore, T cells from combination-treated tumors showed enhanced functionality, with increased tumor necrosis factor-alpha and interferon-gamma production compared with monotherapy groups. Single-cell RNA sequencing revealed polarization of CD4+ T cells toward a T helper cell 1 phenotype in combination-treated tumors.Conclusion The combination of FAP-CD40 and PD1-IL2v offers a promising strategy for treating poorly infiltrated, cold tumors. By driving T cell infiltration, promoting de novo TDC formation and orchestrating local antitumor immunity, this strategy provides a foundation for future therapies targeting immunotherapy-resistant tumors. |
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| Item Description: | Online veröffentlicht: 28. Mai 2026 Gesehen am 30.06.2026 |
| Physical Description: | Online Resource |
| ISSN: | 2051-1426 |
| DOI: | 10.1136/jitc-2025-014620 |