A long-standing problem in tumor immunology that poses a serious challenge for cancer immunotherapy is why tumor-killing CD8+ T cells do not efficiently infiltrate tumors. In stark contrast, CD4+ T cells, especially regulatory T cells, which induce immunosuppression and promote tumor growth and metastasis, accumulate in tumors. Extensive studies from our laboratory and other groups show that STAT3, a Signal Transducer and Activator of Transcription family protein critical for tumor cell survival and invasion, mediates the crosstalk between tumor cells and various immune cells, causing tumor immunosuppression. Over the last five years, our work further establishes a role of STAT3 in impacting both CD8+ and CD4+ T cells in tumor-bearing hosts. Our results suggest that STAT3 activity within CD4+ T cells is critical for their tumor accumulation. By contrast, STAT3 intrinsic to CD8+ T cells inhibits their tumor infiltration. Based on these findings, we hypothesize that tumor recruitment of CD4+ and CD8+ T cells utilizes distinct signaling pathways/factors, resulting in opposing biological functions that enhance tumor progression. In this application, we will test our hypothesis by examining whether signaling of sphingosine-1-phosphate (S1P) and its receptor, S1PR1, which we have demonstrated to be critical for persistent STAT3 activation in tumor cells and tumor-associated immune cells, is essential for CD4+ T cell mobilization to tumor sites. We will also assess whether STAT3 inhibition-induced expression of interferon (IFN) and T cell attractants, also known as chemokines, causes CD8+ T cell tumor infiltration. Moreover, we propose to dissect out detailed molecular mechanisms by which S1P/S1PR1-STAT3 signaling and STAT3 inhibition-induced IFN/chemokine signaling modulate CD4+ and CD8+ T cell mobilization to tumor sites, respectively. Results from our proposed studies will likely generate new knowledge on fundamental mechanisms underlying the imbalance of CD8+ and CD4+ T cells in tumor-bearing hosts, as well as identify new targets to potentially develop paradigm-shifting cancer immunotherapeutic approaches.

Public Health Relevance

The proposed studies seek to provide insights as to why effector CD8+ T cells, even when they are modified and activated ex vivo, do not infiltrate tumors efficiently, and why immunosuppressive/tumor-promoting CD4+ T cells accumulate in tumor sites (both primary and secondary). We will identify the cues for CD4+ and CD8+ T cell mobilization to tumor, and define the fundamental molecular mechanisms governing tumor T cell mobilization to tumor sites. The knowledge we gain from these proposed studies will, in turn, help us to understand how tumors evade immune detection. Ultimately, these findings will lead to new drug targets to design potentially paradigm-shifting immunotherapeutic approaches for cancer treatment.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
5R01CA122976-10
Application #
8830434
Study Section
Transplantation, Tolerance, and Tumor Immunology (TTT)
Program Officer
Mccarthy, Susan A
Project Start
2006-07-01
Project End
2017-04-30
Budget Start
2015-05-01
Budget End
2017-04-30
Support Year
10
Fiscal Year
2015
Total Cost
Indirect Cost
Name
Beckman Research Institute/City of Hope
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

Showing the most recent 10 out of 30 publications