Baiu et al. showed that CD4+ invariant natural killer T cells (iNKT) and autologous or allogeneic monocyte-derived DCs formed stable complexes, with enhanced expression of MHC I, 4-1BBL, OX40L, and IL-15Ra in DCs, and CD70 in iNKT cells. Complexes generated sustained DC signaling and created a platform for antigen-specific CD8+ T cell activation. In a xenograft model of B cell lymphoma, iNKT-DC induced T cell effector differentiation, reduced tumor burden, and remained effective at late disease stages that were resistant to ICB. Patient-derived DCs formed similar conjugates with allogeneic CD4+ iNKT cells and activated tumor antigen-specific CD8+ T cells.
Contributed by Shishir Pant
ABSTRACT: Invariant Natural Killer T (iNKT) cells are a conserved T lymphocyte population capable of acting on dendritic cells (DCs) to potently amplify downstream immune responses. However, the processes underlying such iNKT adjuvancy remain poorly understood. Here, 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 to DCs treated with the synthetic adjuvant monophosphoryl lipid A (MPLA), DCs complexed with iNKT cells had elevated expression of MHC class I and multiple costimulatory molecules including 4-1BBL, OX40L, and IL-15R_, while the iNKT cells expressed CD70. Consistent with this distinctive co-stimulatory 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 Head and Neck Cancer patients 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.
Author Info: (1) University of Wisconsin-Madison, Madison, WI, United States. (2) University of Wisconsin-Madison, Madison, WI, United States. (3) University of Wisconsin-Madison, Madison, WI,
Author Info: (1) University of Wisconsin-Madison, Madison, WI, United States. (2) University of Wisconsin-Madison, Madison, WI, United States. (3) University of Wisconsin-Madison, Madison, WI, United States. (4) University of Wisconsin-Madison, Madison, WI, United States. (5) University of Wisconsin-Madison, Madison, WI, United States. (6) University of Wisconsin-Madison, United States. (7) University of Wisconsin-Madison, Madison, WI, United States. (8) University of Wisconsin-Madison, Madison, WI, United States. (9) (10) University of Wisconsin-Madison, Madison, WI, United States.
