| Autor: |
Delfanti, Gloria, Cortesi, Filippo, Perini, Alessandra, Antonini, Gaia, Azzimonti, Laura, de Lalla, Claudia, Garavaglia, Claudio, Squadrito, Mario L., Fedeli, Maya, Consonni, Michela, Sesana, Silvia, Re, Francesca, Shen, Haifa, Dellabona, Paolo, Casorati, Giulia |
| Předmět: |
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| Zdroj: |
Science Immunology; 2022, Vol. 7 Issue 74, p1-18, 18p |
| Abstrakt: |
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 α-galactosyl ceramide (α-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 α-GalCer boosting as a potential therapy for patients with cancer. TCR-engineered iNKT cells: Adoptive cell therapy has had success in treating various blood cancers. However, in solid tumors, most of these therapies show little efficacy due to exhaustion and poor migration to tumors. Here, Delfanti et al. leveraged natural killer T cells as an adoptive cell therapy platform, specifically producing them to express a TCR specific for a tumor-associated antigen. In mouse models, they found that these TCR-engineered iNKT robustly delayed tumor growth, leading to rejection and prolonged antitumor effects in some mice. These cells migrated well into tumors, killed tumor cells directly, and helped to shift intratumorally myeloid cells to an antitumor phenotype. Boosting TCR-engineered iNKTs with α-GalCer improved antitumor immune responses. Thus, TCR-engineered iNKT cells might be a promising therapy for patients with cancer. [ABSTRACT FROM AUTHOR] |
| Databáze: |
Complementary Index |
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