Modulation of regulatory T cell suppression in tumors through OX40

Burocchi, Alessia (2012). Modulation of regulatory T cell suppression in tumors through OX40. PhD thesis The Open University.



Tumor cells develop numerous mechanisms to escape from the control exerted by the immune system. One of these strategies is the accumulation of regulatory T cells (Treg) within the tumor, which keep effector T cells (Teff) and dendritic cells (DC) in an inactive state. An efficient approach to overcome the inhibitory potential of Treg focuses on OX40, a costimulatory molecule constitutively expressed by Treg and induced in activated Teff. The treatment of mouse transplantable tumor models with the mAb OX86, the agonist of OX40, induces tumor rejection by acting on both these T cell subsets. In this study we investigated the fine cellular mechanisms at the basis of this process, dissecting the effects of OX86 on Treg and on CD4+Foxp3-CD44highCD62LlowOX40+ effector memory T cells (Tem), which represent the most abundant Teff subset in the tumor. Upon OX40 stimulation, Treg are "contra-suppressed" and down-modulate the expression of the transcription factor interferon regulatory factor 1 (IRF1), thus reducing the secretion of IL- 10. Conversely OX86 provides activating stimuli to Tern, which up-regulate CD40L and in turn promote the maturation of DC. OX86 shifts the tumoral milieu from tolerogenic to immunogenic, favoring the activation and migration of DC from the tumor to the draining lymph node (dLN) and the subsequent new CTL induction.

The relevance of OX40 in Treg biology goes beyond the modulation of their suppressive abilities. OX40 increases the sensitivity of Treg to IL-2, facilitating the phosphorylation of STAT5 through high level of the mirl55 and low level of SOCS1. The overexpression of miR155 endowed Treg of higher suppressive functions, further enhancing tumor growth. These data clearly remark the key roles exerted by OX40 in influencing Treg and Teff behavior. Understanding how to manipulate OX40 signaling will provide great advantage in the development of efficient therapy for both tumors and autoimmune diseases.

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