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.
Author Info: (1) Department of Immunology, School of Medicine, UConn Health, Farmington, CT 06030, USA. (2) Department of Immunology, School of Medicine, UConn Health, Farmington, CT 06030, USA
Author Info: (1) Department of Immunology, School of Medicine, UConn Health, Farmington, CT 06030, USA. (2) Department of Immunology, School of Medicine, UConn Health, Farmington, CT 06030, USA. (3) Department of Immunology, School of Medicine, UConn Health, Farmington, CT 06030, USA. (4) Department of Immunology, School of Medicine, UConn Health, Farmington, CT 06030, USA. (5) Department of Immunology, School of Medicine, UConn Health, Farmington, CT 06030, USA. (6) Department of Immunology, School of Medicine, UConn Health, Farmington, CT 06030, USA. (7) Department of Immunology, School of Medicine, UConn Health, Farmington, CT 06030, USA. Electronic address: aadler@uchc.edu. (8) Department of Immunology, School of Medicine, UConn Health, Farmington, CT 06030, USA. Electronic address: vella@uchc.edu. (9) Department of Pathology, Beth Israel Deaconess Medical Center and Harvard Medical School, Boston, Massachusetts.
