Funded R01 Abstract and Specific Aims: T cells are the main effector components of anti-tumor immunity in the majority of cancer types. The phenotypic and functional heterogeneity of memory T cells in the human cancer environment have been the focus of recent studies. We and others have shown that the metabolic alteration in the cancer microenvironment can directly mediate memory and effector T cell dysfunction. However, it is unknown whether nave T cells are targeted and altered by cancer metabolism in patients with cancer, particularly in patients with advanced cancer. PD-L1 and PD-1 blockade and other types of checkpoint therapy target, rescue, and promote effector T cell function to achieve clinical response. However, it is unknown if and how nave T cells are involved in the current cancer immunotherapy-mediated mechanisms. There is a balanced loss and replacement of nave T cells in the periphery. The molecular basis of nave T cell quiescence has been studied in homeostasis in mice. However, the nature of nave T cells is poorly defined in patients with cancer and in tumor bearing mouse models under homeostatic situation and immunotherapeutic settings. Alteration of nave T cells may likely affect T cell homeostasis and memory T cell differentiation and functionality in the tumor bearing hosts. Thus, it is time to systemically study the nature of nave T cells in tumor bearing hosts. In the current proposal, we will investigate the functional and molecular features and therapeutic relevance of nave T cells in patients with ovarian cancer and in several tumor bearing mouse models.
Our specific aims are:
Aim 1 is to test our hypothesis that autophagy malformation is a molecular feature of nave T cells in tumor.
Aim 2 is to determine the molecular mechanisms of FIP200 loss in nave T cells in tumor.
Aim 3 is to test our hypothesis that FIP200 in nave T cells affects spontaneous and therapy-induced tumor immunity.
There are extensive studies in memory T cells in tumor. However, nave T cells are poorly understood in patients with cancer. We will investigate the functional and molecular features and therapeutic relevance of nave T cells in patients with ovarian cancer and in several relevant tumor bearing mouse models.
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| Lin, Heng; Wei, Shuang; Hurt, Elaine M et al. (2018) Host expression of PD-L1 determines efficacy of PD-L1 pathway blockade-mediated tumor regression. J Clin Invest 128:805-815 |
| Nagarsheth, Nisha; Wicha, Max S; Zou, Weiping (2017) Chemokines in the cancer microenvironment and their relevance in cancer immunotherapy. Nat Rev Immunol 17:559-572 |
| Guo, Liang; Zhang, Peng; Chen, Zhimin et al. (2017) Hepatic neuregulin 4 signaling defines an endocrine checkpoint for steatosis-to-NASH progression. J Clin Invest 127:4449-4461 |
| Xia, Houjun; Wang, Wei; Crespo, Joel et al. (2017) Suppression of FIP200 and autophagy by tumor-derived lactate promotes naïve T cell apoptosis and affects tumor immunity. Sci Immunol 2: |
