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

Area of Science:

• Immunology
• Oncology
• Biotechnology

Background:

• Engineered T cell therapies (CAR, TCR) are effective in blood cancers but limited in solid tumors due to antigen escape, immunosuppression, and poor T cell activation.
• Solid tumors present challenges including antigen escape, immunosuppressive microenvironments, and insufficient T cell receptor (TCR) signaling.

Purpose of the Study:

• To develop a novel chimeric costimulatory receptor (ICCR) targeting intercellular adhesion molecule 1 (ICAM1) to enhance T cell activation and overcome limitations in solid tumor treatment.
• To investigate the efficacy of ICCR-engineered T cells in solid tumor models.

Main Methods:

• Engineered T cells expressing an ICAM1-specific chimeric costimulatory receptor (ICCR).
• Assessed ICCR engagement with ICAM1 on tumor cells and its effect on T cell signaling (NFκB, TCR).
• Evaluated ICCR-T cell proliferation, cytokine production, cytotoxicity, and tumor control in anaplastic thyroid cancer xenograft models.

Main Results:

• ICCR engagement with ICAM1 triggered NFκB signaling, augmenting T cell activation independently of TCR/MHC.
• Full T cell activation and cytotoxicity remained dependent on intact TCR signaling.
• ICCR-T cells demonstrated increased proliferation, cytokine production, and cytotoxicity, leading to improved tumor control in preclinical models.

Conclusions:

• ICCR enhances T cell function in solid tumor microenvironments by strengthening tumor cell engagement and amplifying downstream signaling.
• ICCR represents a promising strategy to improve the efficacy of low-activity tumor-specific TCRs in solid tumors.
• This immune synapse-mimetic approach offers a novel therapeutic avenue for solid tumor treatment.