CD8+ T-cell Antitumor Immunity via Human iNKT–DC Conjugates

Invariant NK T (iNKT) cells are a conserved T-lymphocyte population capable of acting on dendritic cells (DC) to potently amplify downstream immune responses. However, the processes underlying such iNKT adjuvancy remain poorly understood. In this study, we showed that allogeneic human CD4+ iNKT cells form stably adhered bi-cellular complexes with monocyte-derived DCs that migrated together as pairs and showed extended DC calcium signaling. Compared with DCs treated with the synthetic adjuvant monophosphoryl lipid A, DCs complexed with iNKT cells had elevated expression of MHC class I and multiple costimulatory molecules, including 4-1BBL, OX40L, and IL15Rα, whereas the iNKT cells expressed CD70. Consistent with this distinctive costimulatory profile, iNKT-DC complexes were efficient activators of CD8+ T cells. Administering iNKT-DC complexes as a cellular immunotherapy in a xenograft model of aggressive human B-cell lymphoma resulted in rapid reduction in tumor mass, antigen-specific B-cell clearance, and transcriptional activation indicative of enhanced T-cell proliferation and effector responses. iNKT-DC immunotherapy was effective at late stages of tumor progression that were refractory to immune checkpoint blockade immunotherapy, suggesting that the consortium of activating signals provided by iNKT-DC complexes rejuvenates exhausted antitumor immunity. Finally, allogeneic CD4+ iNKT cells formed similar complexes with monocyte-derived DCs from patients with head and neck cancer and promoted tumor antigen-dependent CD8+ T-cell activation. These results show that monocyte-derived DCs paired with allogeneic CD4+ iNKT cells act as a potent antitumor cellular immunotherapy that activates antigen-specific CD8+ T-cell immunity.