The tumor microenvironment severely limits the efficacy of various immunotherapies. For adoptive T cell therapy, the need to select/engineer and expand T cells with targeted antigen specificity while still preserving their effector function and homing capacities poses additional challenges. We and others have demonstrated that Stat3, a key oncogenic transcription factor constitutively activated in diverse cancer cells and important for tumor cell survival, is also activated in tumor stromal immune cells and potently immunosuppressive. Our preliminary studies show that targeted Stat3 gene ablation in myeloid cells results in tumor DC activation, tumor Treg cell reduction and heavy infiltration of CD8+ T cells in tumors, leading to effective antitumor immune responses. Furthermore, in mice with a Stat3-/- myeloid compartment, adoptively transferred CD8+ T cells proliferate well and are highly activated in the tumor draining lymph nodes. We were also able to capture live images by multi-photon confocal microscopy of transferred Stat3-/- CD8+ T cells efficiently infiltrating tumors, where they proliferate, leading to activation of tumor antigen-specific immune responses. We have begun to understand the cellular and molecular mechanisms that allow Stat3 in both tumor myeloid cells and T cells to impede T-cell mediated antitumor immunity. In this application, we propose to further define these cellular and molecular mechanisms and thereby identifying additional targets to optimize Stat3 targeting and T cell therapy. To facilitate potential future clinical translation, we will also test two reagents, both of which have shown positive effects on the tumor immunologic environment, for their potential to improve T cell therapies. One is a novel Toll-like receptor (TLR) agonist-siRNA conjugate, a technology platform we have recently developed, and is capable of immune activation and targeted gene silencing of desired immunologic checkpoints such as Stat3 in myeloid and B cells. The other is an FDA-approved tyrosine kinase inhibitor, sunitinib, as our preliminary data suggested it inhibited Stat3 in tumor cells, tumor-infiltrating dendritic cells and myeloid-derived suppressor cells. Additionally, we will test antitumor efficacy by silencing Stat3 in T cells ex vivo with lentiviral-siRNAs. The proposed studies may lead to new strategies to expand and activate transferred T cells in vivo, thereby overcoming several major hurdles facing T cell therapy, and significantly improve its efficacy for cancer treatment.
Targeting Stat3 in tumor cells and immune cells has profound effects on tumors and the potential to activate and expand transferred T cells in vivo. With an FDA-approved tyrosine kinase inhibitor that blocks Stat3 in several types of cells, a novel siRNA approach that targets Stat3 and its key mediators in myeloid cells in tumor, and emergence of small-molecule Stat3 inhibitors, we anticipate that the proposed studies will provide exciting new possibilities for adoptive T-cell transfer cancer immunotherapy.
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|Zhang, Chunyan; Xin, Hong; Zhang, Wang et al. (2016) CD5 Binds to Interleukin-6 and Induces a Feed-Forward Loop with the Transcription Factor STAT3 in B Cells to Promote Cancer. Immunity 44:913-923|
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|Herrmann, Andreas; Cherryholmes, Gregory; Schroeder, Anne et al. (2014) TLR9 is critical for glioma stem cell maintenance and targeting. Cancer Res 74:5218-28|
|Priceman, Saul J; Shen, Shudan; Wang, Lin et al. (2014) S1PR1 is crucial for accumulation of regulatory T cells in tumors via STAT3. Cell Rep 6:992-999|
|Yang, Chunmei; Lee, Heehyoung; Jove, Veronica et al. (2013) Prognostic significance of B-cells and pSTAT3 in patients with ovarian cancer. PLoS One 8:e54029|
|Zhang, Qifang; Hossain, Dewan Md Sakib; Nechaev, Sergey et al. (2013) TLR9-mediated siRNA delivery for targeting of normal and malignant human hematopoietic cells in vivo. Blood 121:1304-15|
|Deng, Jiehui; Liu, Yong; Lee, Heehyoung et al. (2012) S1PR1-STAT3 signaling is crucial for myeloid cell colonization at future metastatic sites. Cancer Cell 21:642-54|
|Lee, Heehyoung; Zhang, Peng; Herrmann, Andreas et al. (2012) Acetylated STAT3 is crucial for methylation of tumor-suppressor gene promoters and inhibition by resveratrol results in demethylation. Proc Natl Acad Sci U S A 109:7765-9|
|Liu, Yong; Deng, Jiehui; Wang, Lin et al. (2012) S1PR1 is an effective target to block STAT3 signaling in activated B cell-like diffuse large B-cell lymphoma. Blood 120:1458-65|
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