NKT cell-targeted vaccination plus anti-4-1BB antibody generates persistent CD8 T cell immunity against B cell lymphoma

Harnessing the immune adjuvant properties of natural killer T (NKT) cells is an effective strategy to generate anti-cancer immunity. The objective of this study was to increase the potency and durability of vaccine-induced immunity against B cell lymphoma by combining alpha-galactosylceramide (α-GalCer)-loaded tumor cell vaccination with an agonistic antibody targeting the immune checkpoint molecule 4-1BB (CD137). We observed potent synergy when combining vaccination and anti-4-1BB antibody treatment resulting in significantly enhanced survival of mice harbouring Eμmyc tumors, including complete eradication of lymphoma in over 50% of mice. Tumor-free survival required IFN-γ-dependent expansion of CD8 T cells and was associated with 4-1BB-mediated differentiation of KLRG1+ effector CD8 T cells. ‘Cured’ mice were also resistant to lymphoma re-challenge 80 days later indicating successful generation of immunological memory. Overall, our results demonstrate that therapeutic anti-cancer vaccination against B cell lymphoma using an NKT cell ligand can be boosted by subsequent co-stimulation through 4-1BB leading to a sustainable immune response that may enhance outcomes to conventional treatment