Recent studies in both mouse and human cancer models have demonstrated that the barrier to effective immunotherapy can be drastically reduced when T cells are transferred into a lymphopenic host. However, to our knowledge, whether homeostatic proliferation constitutes normal host resistance to cancer has never been studied. The poor understanding of the mechanisms of homeostatic proliferation has made it difficult both to elucidate the contribution of homeostatic proliferation to the cancer resistance and to enhance homeostatic proliferation for more efficient cancer immunotherapy. In the last funding period, my laboratory revealed CD24 as a critical checkpoint in regulating homeostatic proliferation of T cells. In the next period, we propose to critically test the importance of homeostatic proliferation in cancer resistance and generate proof-of- principle data on whether CD24 can be targeted to enhance homeostatic proliferation in the setting of cancer therapy. Specifically, we will investigate three issues: First, Does CD24-regulated homeostatic proliferation contribute to mouse resistance to transplanted or carcinogen-induced tumorigenesis? Our preliminary data have demonstrated that CD24-deficient mice exhibit significantly enhanced resistance to syngeneic transplants of tumors, including colon cancer and melanoma cell lines. In addition, our data demonstrated that the CD24-deficient mice were highly resistant to 3-methylcholanthrene (MCA)-induced carcinogenesis and spontaneous prostate cancer. We will determine whether the resistance can be attributed to enhanced homeostatic proliferation in the CD24-deficient mice. We will use lineage-specific ablation of the CD24 gene to test our central hypothesis that CD24-deficiency confer cancer resistance by increasing homeostatic proliferation of T cells. Second, is CD24-mediated homeostatic proliferation essential for effective cancer immunotherapy? We have produced the first transgenic mice that express TCR (P1CTL) specific for a tumor antigen and have used this model to study the basic mechanisms of activation and effector function of tumor reactive T cells over the last 10 years. We will adopt the model to determine whether a targeted mutation of CD24 in the transgenic T cells abrogates the therapeutic effect of P1CTL. Conversely, we will determine whether targeted mutation of CD24 in the lymphopenic recipient will enhance the efficacy of tumor therapy by WT P1CTL. Thirdly, what is the molecular mechanism for cancer resistance in CD24-deficient mice? We have made a novel observation that CD24 binds to, and negative regulate host response to, HMGB1. We will test whether this interaction is responsible for suppressing cancer resistance. In addition, our genetic analysis has revealed that while CD24 expressed in T cells is essential for optimal homeostatic proliferation, removing CD24 from DC will dramatically promote the homeostatic proliferation. To understand the molecular basis for the opposite function of CD24, we will carry out a thorough structural analysis of saccharide associated with DC and T cells by state-of-art mass-spectrometry.
The current proposal takes advantage of two parallel lines of studies that have been ongoing in my laboratory over the last 15 years to test a novel concepts of cancer resistance. The results may also lead to practical approaches to enhancing efficacy of cancer immunotherapy.
|Liu, Yang (2016) Neoantigen: A Long March toward Cancer Immunotherapy. Clin Cancer Res 22:2602-4|
|Wang, Lizhong; Liu, Runhua; Ye, Peiying et al. (2015) Intracellular CD24 disrupts the ARF-NPM interaction and enables mutational and viral oncogene-mediated p53 inactivation. Nat Commun 6:5909|
|Peng, Gong; Liu, Yang (2015) Hypoxia-inducible factors in cancer stem cells and inflammation. Trends Pharmacol Sci 36:374-83|
|Liu, Yang (2014) A VISTA on PD-1H. J Clin Invest 124:1891-3|
|Wang, Yin; Liu, Yan; Tang, Fei et al. (2014) Echinomycin protects mice against relapsed acute myeloid leukemia without adverse effect on hematopoietic stem cells. Blood 124:1127-35|
|Li, Weiquan; Katoh, Hiroto; Wang, Lizhong et al. (2013) FOXP3 regulates sensitivity of cancer cells to irradiation by transcriptional repression of BRCA1. Cancer Res 73:2170-80|
|Katoh, Hiroto; Zheng, Pan; Liu, Yang (2013) FOXP3: genetic and epigenetic implications for autoimmunity. J Autoimmun 41:72-8|
|Yang, Yan; Liu, Chengwen; Peng, Weiyi et al. (2012) Antitumor T-cell responses contribute to the effects of dasatinib on c-KIT mutant murine mastocytoma and are potentiated by anti-OX40. Blood 120:4533-43|
|Tang, Fei; Wu, Qi; Ikenoue, Tsuneo et al. (2012) A critical role for Rictor in T lymphopoiesis. J Immunol 189:1850-7|
|Wang, Yin; Liu, Yan; Malek, Sami N et al. (2011) Targeting HIF1Î± eliminates cancer stem cells in hematological malignancies. Cell Stem Cell 8:399-411|
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