OX40 and OX40L Interaction in Cancer

Background: OX40 (CD134) and its binding partner, OX40L (CD252), are expressed on activated CD4, CD8 T-cells, and several other lymphoid and non-lymphoid cells. OX40L belongs to a TNF family member, a 34 kDa type II transmembrane protein. The crystallized complex of human OX40 and OX40L is a trimeric contableuration of one OX40L (trimer) and three OX40 monomers. OX40 and OX40L regulate cytokine production from T-cells, antigen-presenting cells, and natural killer (NK) cells, and modulate cytokine receptor signaling. Methods: In this review, an updated overview of the structural features of OX40/OX40L and their interactions with cancer are provided. Results: Recent studies have shown that stimulation of OX40 is useful for therapeutic immunization strategies for cancer. OX40 serves as a secondary costimulatory immune checkpoint molecule; the binding of OX40 to its ligand enhances the augmentation, survival, memory formation, effector function, and recall responses of both CD4⁺ and CD8⁺ T-cells. Conclusion: This review highlights that OX40-OX40L interactions play crucial roles in both CD4⁺ and CD8⁺ T-cells. Signals through OX40 can abolish the suppressive activity of Tregs, prevent the induction of Tregs from effector T-cells, reduce Foxp3 expression, and induce the proliferation of memory and effector T lymphocytes. Additionally, when transferred into tumor-bearing recipients, they generate proliferation capability and successfully eliminate the established tumor.