Signaling Through OX40 Enhances Antitumor Immunity

Abstract

The existence of tumor-specific T cells, as well as their ability to be primed in cancer patients confirms that the immune response can be deployed to combat cancer. However, there are obstacles that must be overcome to convert the ineffective immune response commonly found in the tumor environment to one that leads to sustained destruction of tumor. Members of the tumor necrosis factor (TNF) superfamily direct diverse immune functions. OX40 and its ligand, OX40L, are key TNF members that augment T-cell expansion, cytokine production, and survival. OX40 signaling also controls regulatory T cell differentiation and suppressive function. Studies over the past decade have demonstrated that OX40 agonists enhance anti-tumor immunity in preclinical models using immunogenic tumors; however, treatment of poorly immunogenic tumors has been less successful. Combining strategies that prime tumor-specific T cells together with OX40 signaling could generate and maintain a therapeutic anti-tumor immune response.

TNF superfamily receptor OX40 triggers invariant NKT cell pyroptosis and liver injury

“…Thus, the exact molecular complex assembled downstream of OX40 stimulation in favor of MALT1 activities requires further clarification. Nevertheless, considering the emerging clinical trials of OX40 agonists in the clinic as cancer immunotherapy reagents (46,47), the role of direct OX40 stimulation in pyroptotic death of iNKT cells provides a note of caution on potential liver damage, and further studies in this area will undoubtedly be important in future development of OX40-directed therapies.…”

T Cell Costimulation with Anti-CD137 Monoclonal Antibodies Is Mediated by K63–Polyubiquitin-Dependent Signals from Endosomes

“…Immunotherapy based on agonist mAbs that engage surface receptors of the TNFR superfamily on cells of the immune system is still in its infancy in terms of clinical trials and with regard to the precise elucidation of the mechanisms of action (17,50,51). In this report, we have addressed the study of the early signaling events triggered by the engagement of CD137 with specific agonist mAbs that elicit a therapeutic response.…”

Cyclophosphamide Induces a Type I Interferon–Associated Sterile Inflammatory Response Signature in Cancer Patients' Blood Cells: Implications for Cancer Chemoimmunotherapy

“…CD69 is an early membrane receptor transiently expressed upon lymphocyte activation and modulating inflammatory responses. OX40 and its ligand, OX40L, are TNF family members that augment expansion, cytokine production, and survival of CD4 þ and CD8 þ T cells, whose signaling has been shown to enhance antitumor immunity and inhibit suppression by Tregs (48). Noticeably, the observed augmented expression of IL-8 receptor in T cells was accompanied by an early increase in IL-8 plasma levels, which may therefore amplify the inflammatory response to cyclophosphamide.…”