The exquisite sensitivity and specificity of T cells for their targets offers considerable promise for the use of immunotherapy in cancer control. However, in many instances, T cells found within tumors are dysfunctional. A major cause for this dysfunctional state is the expression of inhibitory molecules. We have found that the expression of inhibitory molecules by both murine and human tumor infiltrating CD8+ cytotoxic T cells correlates strongly with the expression of the transcription factor BLIMP-1. In this application we show that tumor infiltrating CD8+ T cells over-express BLIMP-1 compared to CD8+ T cells responding to acute viral infection. We show that limiting BLIMP-1 expression in tumor infiltrating lymphocytes results in reduced inhibitory molecule expression and increased functional activity. Further, we show that BLIMP-1 expression controls CD8+ T cell function beyond the expression of inhibitory molecules. From these data, we propose to pursue studies that will define how BLIMP-1 expression is regulated in tumor infiltrating lymphocytes, and will determine how BLIMP-1 expression regulates tumor infiltrating lymphocyte function. The studies presented here will illuminate the mechanisms behind tumor infiltrating lymphocyte dysfunction, and will provide opportunities to develop interventions that either prevent dysfunction, or restore activity.

Public Health Relevance

Tumor infiltrating lymphocytes have the potential to be of profound benefit in controlling the outgrowth of tumors. The studies presented in this proposal are designed to understand how a molecule, known as BLIMP-1, regulates the functional status of these lymphocytes, and how BLIMP-1 is regulated itself in tumor infiltrating lymphocytes.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
3R01CA166458-02S1
Application #
8844054
Study Section
Program Officer
Lin, Alison J
Project Start
2014-07-01
Project End
2017-12-31
Budget Start
2014-07-01
Budget End
2014-12-31
Support Year
2
Fiscal Year
2014
Total Cost
$43,539
Indirect Cost
$10,830
Name
University of Virginia
Department
Pathology
Type
Schools of Medicine
DUNS #
065391526
City
Charlottesville
State
VA
Country
United States
Zip Code
22904