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An ICAM1-Targeting Chimeric Costimulatory Receptor Mimics the Immune Synapse and Enhances Tumor-Specific T-cell Function.

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Τίτλος: An ICAM1-Targeting Chimeric Costimulatory Receptor Mimics the Immune Synapse and Enhances Tumor-Specific T-cell Function.
Συγγραφείς: Min IM; Department of Radiology, Houston Methodist Research Institute, Houston, Texas.; Department of Radiology, Weill Cornell Medicine, New York, New York.; Department of Surgery, Weill Cornell Medicine, New York, New York., Yang Y; Department of Radiology, Houston Methodist Research Institute, Houston, Texas.; Department of Radiology, Weill Cornell Medicine, New York, New York., Stefanova D; Department of Surgery, Weill Cornell Medicine, New York, New York., Vedvyas Y; Department of Radiology, Houston Methodist Research Institute, Houston, Texas.; Department of Radiology, Weill Cornell Medicine, New York, New York., Babu DS; Department of Radiology, Houston Methodist Research Institute, Houston, Texas., Lee DH; Department of Radiology, Houston Methodist Research Institute, Houston, Texas., Alcaina Y; Department of Radiology, Weill Cornell Medicine, New York, New York., Riascos MC; Department of Surgery, Weill Cornell Medicine, New York, New York., Puc J; AffyImmune Therapeutics, Inc., Natick, Massachusetts., Chen KJ; Department of Surgery, Weill Cornell Medicine, New York, New York., Gonzalez-Valdivieso J; Department of Radiology, Weill Cornell Medicine, New York, New York., Thaiparambil J; Department of Radiology, Houston Methodist Research Institute, Houston, Texas., Bilal M; Department of Pathology and Laboratory Medicine, Weill Cornell Medicine, New York, New York., He B; Department of Pathology and Laboratory Medicine, Weill Cornell Medicine, New York, New York., Burnett AC; Department of Radiology, Houston Methodist Research Institute, Houston, Texas., Zarnegar R; Department of Surgery, Weill Cornell Medicine, New York, New York., Fahey TJ 3rd; Department of Surgery, Weill Cornell Medicine, New York, New York., Jin MM; Department of Radiology, Houston Methodist Research Institute, Houston, Texas.; Department of Radiology, Weill Cornell Medicine, New York, New York.
Πηγή: Cancer immunology research [Cancer Immunol Res] 2026 Jul 02; Vol. 14 (7), pp. 1133-1149.
Τύπος έκδοσης: Journal Article
Γλώσσα: English
Στοιχεία περιοδικού: Publisher: American Association for Cancer Research Country of Publication: United States NLM ID: 101614637 Publication Model: Print Cited Medium: Internet ISSN: 2326-6074 (Electronic) Linking ISSN: 23266066 NLM ISO Abbreviation: Cancer Immunol Res Subsets: MEDLINE
Imprint Name(s): Original Publication: Philadelphia, PA : American Association for Cancer Research, [2013]-
Ιατρικοί όροι (MeSH): Intercellular Adhesion Molecule-1*/immunology , Intercellular Adhesion Molecule-1*/metabolism , Immunological Synapses*/immunology , T-Lymphocytes*/immunology , T-Lymphocytes*/metabolism , Receptors, Chimeric Antigen*/immunology , Receptors, Chimeric Antigen*/metabolism , Immunotherapy, Adoptive*/methods, Receptors, Antigen, T-Cell/immunology ; Receptors, Antigen, T-Cell/metabolism ; Lymphocyte Activation/immunology ; Humans ; Animals ; Mice ; Signal Transduction ; Cell Line, Tumor ; Xenograft Model Antitumor Assays
Περίληψη: Engineered T-cell therapies, such as chimeric antigen receptor (CAR)- and T-cell receptor (TCR)-based approaches, have transformed outcomes in hematologic malignancies, yet their efficacy in solid tumors remains limited by tumor antigen escape, immunosuppressive microenvironments, and insufficient activation of CAR or TCR signaling. To overcome these barriers, we developed an intercellular adhesion molecule 1 (ICAM1)-specific chimeric costimulatory receptor (ICCR) engineered for expression in T cells to augment their activation. ICAM1 is broadly expressed across solid tumors and is further upregulated by IFNγ released during early T-cell engagement, creating a feed-forward loop that reinforces tumor recognition. ICCR engagement with ICAM1 triggered NF-κB signaling independently of TCR-peptide (p)/MHC engagement; however, full T-cell activation and cytotoxic function remained dependent on intact TCR signaling. In primary T cells, ICCR increased proliferation, cytokine production, and cytotoxicity, resulting in improved tumor control in two anaplastic thyroid cancer xenograft models treated with allogeneic or autologous ICCR-T cells. Mechanistically, ICCR strengthened tumor cell engagement, promoted selection and expansion of tumor-specific TCR clonotypes, and amplified downstream signaling pathways. These findings identify ICCR as a strategy that leverages an immune synapse-mimetic mechanism to enhance the function of low-activity tumor-specific TCRs and improve T-cell responses in solid tumor microenvironments.
(©2026 American Association for Cancer Research.)
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Grant Information: R01 CA254035 United States CA NCI NIH HHS; R21 CA280566 United States CA NCI NIH HHS; COR9 Emerson Collective (Emerson); R01CA254035 National Cancer Institute (NCI)
Substance Nomenclature: 126547-89-5 (Intercellular Adhesion Molecule-1)
0 (Receptors, Chimeric Antigen)
0 (Receptors, Antigen, T-Cell)
0 (ICAM1 protein, human)
Entry Date(s): Date Created: 20260427 Date Completed: 20260702 Latest Revision: 20260813
Update Code: 20260813
PubMed Central ID: PMC13357678
DOI: 10.1158/2326-6066.CIR-25-0529
PMID: 42043451
Βάση Δεδομένων: MEDLINE
Περιγραφή
ISSN:2326-6074
DOI:10.1158/2326-6066.CIR-25-0529