Tumors have adapted diverse strategies to evade immune surveillance and destruction. It has become increasingly evident that both innate and adaptive immunity maintain networks that suppress natural and immunotherapy-induced antitumor immune responses. Consequently, to achieve effective antitumor immunity, it is essential to first disable these immune suppressive networks. Several recent studies demonstrate a key role of T regulatory cells (Tregs) in sustaining the immune suppressive environment in tumors. Tregs accumulate in tumors and inhibit proliferation and function of CD8+ effector cells at the tumor site. Although dysfunctional dendritic cells (DCs) are associated with Treg expansion in tumors, the underlying molecular mechanisms of Treg accumulation in tumors remain unclear. A few years ago, while validating Stat3 as a target for cancer therapy in animal models, we unexpectedly discovered a direct link between oncogenesis and tumor immune suppression. Stat3, which is constitutively activated by oncoproteins in many cancers, not only inhibits expression of immunologic stimulating molecules but also promotes production of immune suppressive factors. Our recent work further reveals that Stat3-induced tumor suppressive factors activate Stat3 in DCs in the tumor microenvironment, rendering them dysfunctional. Moreover, Stat3 is also constitutively activated in tumor-infiltrating Tregs. Inhibiting Stat3 in the hematopoietic system activates DCs, CD8+ T cells, and notably, a reduction in Tregs and increased infiltration of CD8+ T cells at the tumor site, leading to a robust, CD8+ T cell- mediated, antitumor response. Here, we hypothesize that Stat3 activation in both DCs and T cells is critical for induction and maintenance of tumor Tregs, and as a result Stat3 is an effective target for enhancing DC and T-cell based cancer immunotherapy approaches. To test this hypothesis, we will determine whether dysfunctional DCs generated by Stat3 activation are crucial for expansion of tumor-infiltrating Tregs. We further propose to test whether accumulation of tumor Tregs requires intrinsic Stat3 signaling and, finally, whether Stat3 inhibition in CD8+ T cells renders them resistant to Treg-induced suppression. If our hypothesis is correct, inhibiting Stat3 in these subsets of immune cells will disrupt the immune suppressive networks, thereby enhancing the efficacy of DC and T-cell based immunotherapies. ? ? ?
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