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.

Public Health Relevance

T cells are the main effector components of anti-tumor immunity in the majority of cancer types. There are extensive studies in memory T cells in tumor. However, nave T cells are poorly understood in patients with cancer, particularly in patients with advanced cancer. It is generally thought that nave T cells are localized in peripheral blood and lymph nodes including tumor draining lymph nodes, rather than the tumor microenvironment. Notably, memory T cells are differentiated from nave T cells. If the phenotype and function of memory T cells are altered in tumor, it is possible that this is derived from dysfunctional nave T cells. Furthermore, there is a balanced loss and replacement of nave T cells in the periphery. The nature of nave T cells is poorly defined in patients with cancer. It is thought that immunotherapy target, rescue, and promote effector memory cell function to achieve clinical responses. However, it is unknown if and how nave T cells are involved in the current cancer immunotherapy-mediated mechanisms. 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.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
1R01CA217510-01
Application #
9348840
Study Section
Cancer Immunopathology and Immunotherapy Study Section (CII)
Program Officer
Mccarthy, Susan A
Project Start
2017-08-01
Project End
2022-07-31
Budget Start
2017-08-01
Budget End
2018-07-31
Support Year
1
Fiscal Year
2017
Total Cost
Indirect Cost
Name
University of Michigan Ann Arbor
Department
Surgery
Type
Schools of Medicine
DUNS #
073133571
City
Ann Arbor
State
MI
Country
United States
Zip Code
48109