IFNγ-induced antigen loss in chimeric antigen receptor-T cell therapy

Area of Science:

• Immunology
• Oncology
• Cancer Therapy

Background:

• Chimeric antigen receptor (CAR)-expressing T cell therapies (CARTs) have transformed blood cancer treatment but are ineffective against solid tumors like colorectal cancer (CRC).
• Guanylyl cyclase C (GUCY2C) is a promising target for CRC immunotherapies, including CART and bispecific T-cell engager (BiTE) therapies.
• Interferon-gamma (IFNγ) is crucial for T cell effector functions and CAR T-cell efficacy in solid tumors.

Purpose of the Study:

• To investigate the mechanisms of GUCY2C antigen loss in CRC cells when exposed to activated CART cells.
• To identify novel strategies to overcome antigen loss and enhance the efficacy of immunotherapies targeting solid tumors.

Main Methods:

• Utilized in vitro co-culture systems, conditioned media experiments, cytokine screening, pharmacologic inhibition, CRISPR-Cas9 knockout, and transcriptomic analyses.
• Investigated the role of IFNγ and its downstream signaling pathways in mediating GUCY2C antigen loss.

Main Results:

• Identified a novel mechanism where IFNγ secreted by activated CART cells induces GUCY2C antigen loss in bystander CRC cells.
• This antigen loss is mediated by IFNγ receptor, JAK, and cellular stress signaling pathways.
• Demonstrated that blocking IFNγ signaling with neutralizing antibodies, JAK inhibitors (ruxolitinib), or ER stress relievers (4-phenylbutyrate) can rescue GUCY2C expression.

Conclusions:

• IFNγ negatively impacts immunotherapies targeting native surface antigens like CART and BiTE therapies by inducing antigen loss.
• Disrupting stress signaling pathways offers a promising strategy to reverse IFNγ-mediated antigen loss and enhance the effectiveness of solid tumor immunotherapies.