OX40 agonists enhance CD4-positive T-cell cytotoxic activity against advanced melanoma.
Major finding: OX40 agonists enhance CD4-positive T-cell cytotoxic activity against advanced melanoma.
Mechanism: OX40 ligation induces T cells with cytolytic and memory features and eomesodermin expression.
Impact: This approach may allow for selection of potent antitumor T cells for adoptive T-cell therapy.
Recent studies suggest that the use of CD4-positive T cells and activation of T-cell costimulatory molecules, such as TNF receptor superfamily member 4 (TNFRSF4, or OX40), may improve the clinical efficacy of adoptive T-cell therapy in treating melanoma. In addition, chemotherapeutic agents that induce lymphopenia also increase the antitumor potency of immunotherapy and confer cytolytic activity to CD4-positive T cells. Hirschhorn-Cymerman and colleagues investigated whether OX40 engagement under lymphopenic conditions enhanced the cytotoxic activity of CD4-positive T cells against advanced melanoma. Treatment of tumor-bearing mice with an anti-OX40 agonist, melanoma-specific CD4-positive T cells, and cyclophosphamide was more effective than melanoma-specific CD8-positive T cells alone and resulted in the eradication of these established tumors. This augmented antitumor activity did not require endogenous adaptive immune cells and was dependent on tumor antigen expression; however, this approach also stimulated a potent bystander killing effect in tumor cells lacking antigen expression. Triple combination therapy also triggered selective elimination of immunosuppressive regulatory T cells and an increase in effector T cells (Teff), as well as upregulation of the Teff master regulator eomesodermin, suggesting that OX40 activation reprograms CD4-positive T cells to promote cytotoxic activity. Indeed, treated Teff cells expressed markers of both terminally differentiated cytolytic cells and memory T cells and exhibited a distinct cytokine profile characterized by secretion of T helper (Th) 1 and Th2 cytokines. Furthermore, exposure of melanoma-specific human CD4-positive T cells derived from patients to OX40 agonists augmented the killing of matched melanoma cell lines in vitro. These results support the use of immunomodulatory antibodies such as OX40 agonists to engineer antitumor cells with greater potency and to improve the clinical success of adoptive T-cell transfer in cancer treatment.