Morales Del Valle et al. developed a mouse model chronically exposing a tumor-unrelated antigen on MHC-II+CD11c+ DCs, and showed that antigen-specific CD4+ T cells can differentiate into effectors in the presence of dual costimulation with OX40 and 4-1BB agonists. These antigen-specific CD4+ T cells retained their therapeutic helper function, expressed IFNγ in a TCR-independent manner upon stimulation with a JAK/STAT activating cytokine (IL-2 or IL-12) plus an IL-1 family cytokine (IL-33 or IL-36), and, upon adoptive transfer, conferred an antitumor response in the presence of intratumoral IL-36 and subsequent dual costimulation.
Chronic exposure to tumor-associated antigens inactivates cognate T cells, restricting the repertoire of tumor-specific effector T cells. This problem was studied here by transferring TCR transgenic CD4 T cells into recipient mice that constitutively express a cognate self-antigen linked to MHC II on CD11c-bearing cells. Immunotherapeutic agonists to CD134 plus CD137, "dual costimulation," induces specific CD4 T cell expansion and expression of the receptor for the Th2-associated IL-1 family cytokine IL-33. Rather than producing IL-4, however, they express the tumoricidal Th1 cytokine IFNgamma when stimulated with IL-33 or IL-36 (a related IL-1 family member) plus IL-12 or IL-2. IL-36, which is induced within B16-F10 melanomas by dual costimulation, reduces tumor growth when injected intratumorally as a monotherapy and boosts the efficacy of tumor-nonspecific dual costimulated CD4 T cells. Dual costimulation thus enables chronic antigen-exposed CD4 T cells, regardless of tumor specificity, to elaborate tumoricidal function in response to tumor-associated cytokines.