Abstract
OX40 is a costimulatory receptor that potentiates proliferation, survival, memory formation, and effector function of CD4+ and CD8+ T-cells, while overcoming the suppressive activity of regulatory T-cells (Tregs). Here, we explored the combination of an OX40L fusion protein (OX40L-FP) with a poxvirus-based cancer vaccine (MVA-Twist-TRICOM) to inhibit tumor metastasis in the 4T1 murine breast cancer model.Contrary to the single agent treatments, the combination therapy significantly decreased the number of metastatic colonies per lung and prolonged survival. Depletion studies demonstrated that these effects were mediated by both CD4+ and CD8+ T-cells. The combination therapy a) increased the total number of T-cells in the CD4+Foxp3- population and the CD4+ central and effector memory subsets within the lung, spleen, and draining lymph node, b) enhanced infiltration of CD4+ T-cells into metastatic areas of the lung, and (c) increased the number of functional CD8+ T-cells that produced IFNγ and TNFα. The combination therapy also promoted the development of KLRG1-CD127+ memory precursor CD8+ T-cells, while reducing those with a KLRG1+ terminally differentiated phenotype. Moreover, the combination of OX40L-FP and vaccine induced greater CD4+ and CD8+ Twist-specific responses. In addition, Tregs isolated from mice receiving the combination were also less immunosuppressive in ex-vivo proliferation assays than those from the OX40L-FP and MVA-Twist-TRICOM monotherapy groups. Such results provide the rationale to combine co-stimulatory agonists with cancer vaccines for the treatment of tumor metastasis.
Highlights
OX40 (CD134) is a co-stimulatory receptor within the tumor necrosis factor receptor (TNFR) superfamily that is widely known to augment adaptive immune responses [1]
These costimulatory agents have been combined with tumor cell lysate and tumor-associated peptide vaccine platforms supplemented with anti-CD40 mAbs and TLR ligands that enhance antigen presentation by dendritic cells (DCs) [21,22,23]
OX40 agonists have been combined with DC vaccines pulsed with soluble protein or apoptotic tumor cells [24], and with whole tumor cell vaccines secreting granulocyte-macrophage colony-stimulating factor (GMCSF) [13, 25]
Summary
OX40 (CD134) is a co-stimulatory receptor within the tumor necrosis factor receptor (TNFR) superfamily that is widely known to augment adaptive immune responses [1]. Its expression is transiently induced on CD4+ and CD8+ T-cells by TCR stimulation, and can peak anywhere from 24 hours to 4-5 days after antigen recognition. The ligand of OX40 (OX40L) is expressed on activated antigen-presenting cells (APCs), including B-cells, dendritic cells (DCs), and macrophages after CD40 ligation. OX40-OX40L interactions enhance the expansion, survival, memory formation, effector function, and recall responses of both CD4+ and CD8+ T-cells [27]. Targeting OX40 with exogenous agonists can significantly enhance anti-tumor immunity by overcoming self-tolerance and immunosuppressive mechanisms that contribute to tumor-induced T-cell anergy [3]. Cancer vaccines are attractive in combination with OX40 agonists based on their ability to overcome inadequate immune stimulation and increase the frequency of tumor-reactive T-cell populations. OX40 agonists may further enhance the proliferation and activity of antigenspecific T-cell populations generated upon vaccination to elicit robust anti-tumor immunity
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