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¹ Department of Experimental Pathology, Institute for Frontier Medical Sciences, Kyoto University
² Department of Gastroenterology, Kyoto University Hospital, Kyoto 606-8507, Japan
³ National Institute for Longevity Sciences, National Center for Geriatrics and Gerontology, Aichi 474-8522, Japan
⁴ Core Research for Evolutional Science and Technology (CREST), Japan Science and Technology Agency Kawaguchi 332-0012, Japan

CORRESPONDENCE Shimon Sakaguchi: shimon{at}frontier.kyoto-u.ac.jp

T cell stimulation via glucocorticoid-induced tumor necrosis factor receptor family–related protein (GITR) can evoke effective tumor immunity. A single administration of agonistic anti-GITR monoclonal antibody (mAb) to tumor-bearing mice intravenously or directly into tumors provoked potent tumor-specific immunity and eradicated established tumors without eliciting overt autoimmune disease. A large number of CD4⁺ and CD8⁺ T cells, including interferon (IFN)-–secreting cells, infiltrated regressing tumors. Tumor-specific IFN-–secreting CD4⁺ and CD8⁺ T cells also increased in the spleen. The treatment led to tumor rejection in IFN-–intact mice but not IFN-–deficient mice. Furthermore, coadministration of anti-GITR and anti–CTLA-4 mAbs had a synergistic effect, leading to eradication of more advanced tumors. In contrast, coadministration of anti-CD25 and anti-GITR mAbs was less effective than anti-GITR treatment alone, because anti-CD25 depleted both CD25⁺-activated effector T cells and CD25⁺CD4⁺ naturally occurring regulatory T (T reg) cells. Importantly, CD4⁺ T cells expressing the T reg–specific transcription factor Foxp3 predominantly infiltrated growing tumors in control mice, indicating that tumor-infiltrating natural Foxp3⁺CD25⁺CD4⁺ T reg cells may hamper the development of effective tumor immunity. Taken together, T cell stimulation through GITR attenuates T reg–mediated suppression or enhances tumor-killing by CD4⁺ and CD8⁺ effector T cells, including those secreting IFN-, or both. Agonistic anti-GITR mAb is therefore instrumental in treating advanced cancers.

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