TCR-engineered iNKT cells induce robust antitumor response by dual targeting cancer and suppressive myeloid cells

Adoptive immunotherapy with T cells engineered with tumor-specific T cell receptors (TCRs) holds promise for cancer treatment. However, suppressive cues generated in the tumor microenvironment (TME) can hinder the efficacy of these therapies, prompting the search for strategies to overcome these detrimental conditions and improve cellular therapeutic approaches. CD1d-restricted invariant natural killer T (iNKT) cells actively participate in tumor immunosurveillance by restricting suppressive myeloid populations in the TME. Here, we showed that harnessing iNKT cells with a second TCR specific for a tumor-associated peptide generated bispecific effectors for CD1d-and major histocompatibility complex (MHC)-restricted antigens in vitro. Upon in vivo transfer, TCR-engineered iNKT (TCR-iNKT) cells showed the highest efficacy in restraining the progression of multiple tumors that expressed the cognate antigen compared with nontransduced iNKT cells or CD8(+) T cells engineered with the same TCR. TCR-iNKT cells achieved robust cancer control by simultaneously modulating intratumoral suppressive myeloid populations and killing malignant cells. This dual antitumor function was further enhanced when the iNKT cell agonist alpha-galactosyl ceramide (alpha-GalCer) was administered as a therapeutic booster through a platform that ensured controlled delivery at the tumor site, named multistage vector (MSV). These preclinical results support the combination of tumor-redirected TCR-iNKT cells and local alpha-GalCer boosting as a potential therapy for patients with cancer.

Automated summary

Adoptive immunotherapy using T cells engineered with tumor-specific TCRs holds promise for cancer treatment. In this study, researchers harnessed iNKT cells with a second TCR specific for a tumor-associated peptide to generate bispecific effectors for CD1d- and MHC-restricted antigens. The TCR-engineered iNKT cells demonstrated high efficacy in restraining tumor progression and achieved robust cancer control by simultaneously modulating intratumoral suppressive myeloid populations and killing malignant cells. These findings support the potential use of tumor-redirected TCR-iNKT cells and local alpha-GalCer boosting as a therapy for cancer patients.