OX40 triggering blocks suppression by regulatory T cells and facilitates tumor rejection.
Regulatory T (T reg) cells are the major obstacle to cancer immunotherapy, and their depletion promptly induces conversion of peripheral precursors into T reg cells. We show that T reg cells can be functionally inactivated by OX40 triggering. In tumors, the vast majority of CD4(+) T cells are Foxp3(+) and OX40(bright). However, intratumor injection of the agonist anti-OX40 monoclonal antibody (mAb) OX86, but not anti-CD25 mAb, induces tumor rejection in 80% of mice, an effect that is abrogated by CD8 depletion. Upon intratumor OX40 triggering, increased numbers of infiltrating dendritic cells (DCs) migrate to draining lymph nodes and generate a new wave of tumor-specific cytotoxic T lymphocytes, as detected by tetramer and CD44 staining of node CD8(+) T lymphocytes. Tumor-bearing Rag1-knockout (KO) mice reconstituted with OX40-deficient T reg cells and wild-type (WT) effector T cells, or the reciprocal combination, showed that both T reg and effector T cells must be triggered via OX40 for the tumor to be rejected. Accordingly, WT but not OX40-KO mice receiving intratumor coinjection of OX86 and ovalbumin protein were able to revert tumor-induced tolerization of adoptively transferred OX40-competent OTII T lymphocytes. In conclusion, OX40-mediated inactivation of T reg cell function unleashes nearby DCs, allowing them to induce an adaptive immune response. In addition, the known OX40-dependent delivery of fitness signals to activated T cells is boosted by concurrent T reg cell inhibition. OX40 triggering thus has multiple effects that converge to mediate tumor rejection.
Piconese
Silvia
S
Immunotherapy and Gene Therapy Unit, Department of Experimental Oncology, Fondazione IRCCS Istituto Nazionale dei Tumori, 20133 Milan, Italy.
Valzasina
Barbara
B
Colombo
Mario P
MP
D000818:Animals; D000911:Antibodies, Monoclonal / Q000276:immunology; D000951:Antigens, Neoplasm / Q000276:immunology; D002465:Cell Movement; D045142:Cross-Priming; D003713:Dendritic Cells / Q000166:cytology; D007109:Immunity; D008198:Lymph Nodes; D016246:Lymphocytes, Tumor-Infiltrating; D051379:Mice; D018345:Mice, Knockout; D009368:Neoplasm Transplantation; D009369:Neoplasms / Q000276:immunology*; D054400:Receptors, CCR7 / Q000172:deficiency; D053262:Receptors, OX40 / Q000276:immunology*; D013602:T-Lymphocytes, Cytotoxic / Q000276:immunology; D050378:T-Lymphocytes, Regulatory / Q000276:immunology*
D000911:Antibodies, Monoclonal; D000951:Antigens, Neoplasm; C515371:Ccr7 protein, mouse; D054400:Receptors, CCR7; D053262:Receptors, OX40