T-cells modified with CD70 as an alternative cellular vaccine for antitumor immunity

Abstract

Abstract Successful tumor eradication primarily depends on generation and maintenance of a large population of tumor-reactive CD8 T-cells. Dendritic cells (DCs) have applied to clinics as potent antitumor therapeutic agents. However, high cost and difficulty in obtaining sufficient amounts for clinical use are the crucial drawbacks of DC-based vaccines. Here, antigenic peptide-loaded T-cells transfected with retrovirus encoding costimulatory ligands CD70, CD80, OX40L, or 4-1BBL were assessed for antigen-specific CD8 T-cell responses, and evaluated antitumor effects along with immunization of a mixture of synthetic peptides, poly-IC and anti-CD40 antibodies (TriVax). T-cells expressing CD70 (CD70-T) exhibited similar level of stimulatory functionality and therapeutic efficacy as DCs. Moreover, CD70-T prime followed by TriVax booster heterologous vaccination elicited therapeutic antitumor effect against B16 melanoma where mediated by CD8 T-cells but not CD4 T-cells or NK cells. The combination with PD-L1 blockade led to potent therapeutic efficacy which exhibited increased tumor infiltrating CD8 T-cells. CD70-T pulsed with multi-antigenic peptide generated multiple antigen-specific polyvalent CD8 T-cells that were capable of inhibiting tumor growth effectively. Moreover, CD70-T vaccination resulted in higher expansion and migration of adoptively transferred T-cells into tumor sites, and elicits enhanced therapeutic effects with peptide-based booster immunization. These results imply that T-cells endowed with CD70 enable the design of effective vaccination strategies against solid cancer, which may overcome current limitations of DC-based vaccines.