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.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
5R01CA122976-04
Application #
7623600
Study Section
Transplantation, Tolerance, and Tumor Immunology (TTT)
Program Officer
Mccarthy, Susan A
Project Start
2006-07-01
Project End
2011-05-31
Budget Start
2009-06-01
Budget End
2010-05-31
Support Year
4
Fiscal Year
2009
Total Cost
$291,277
Indirect Cost
Name
City of Hope/Beckman Research Institute
Department
Type
DUNS #
027176833
City
Duarte
State
CA
Country
United States
Zip Code
91010
Wang, Tianyi; Fahrmann, Johannes Francois; Lee, Heehyoung et al. (2018) JAK/STAT3-Regulated Fatty Acid ?-Oxidation Is Critical for Breast Cancer Stem Cell Self-Renewal and Chemoresistance. Cell Metab 27:136-150.e5
Wang, Tianyi; Fahrmann, Johannes Francois; Lee, Heehyoung et al. (2018) JAK/STAT3-Regulated Fatty Acid ?-Oxidation Is Critical for Breast Cancer Stem Cell Self-Renewal and Chemoresistance. Cell Metab 27:1357
Kammertoens, Thomas; Friese, Christian; Arina, Ainhoa et al. (2017) Tumour ischaemia by interferon-? resembles physiological blood vessel regression. Nature 545:98-102
Herrmann, Andreas; Lahtz, Christoph; Nagao, Toshikage et al. (2017) CTLA4 Promotes Tyk2-STAT3-Dependent B-cell Oncogenicity. Cancer Res 77:5118-5128
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
Zhang, Wang; Zhang, Chunyan; Li, Wenzhao et al. (2015) CD8+ T-cell immunosurveillance constrains lymphoid premetastatic myeloid cell accumulation. Eur J Immunol 45:71-81
Yue, Chanyu; Shen, Shudan; Deng, Jiehui et al. (2015) STAT3 in CD8+ T Cells Inhibits Their Tumor Accumulation by Downregulating CXCR3/CXCL10 Axis. Cancer Immunol Res 3:864-870
Herrmann, Andreas; Priceman, Saul J; Swiderski, Piotr et al. (2014) CTLA4 aptamer delivers STAT3 siRNA to tumor-associated and malignant T cells. J Clin Invest 124:2977-87
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; Pal, Sumanta et al. (2013) B cells promote tumor progression via STAT3 regulated-angiogenesis. PLoS One 8:e64159

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