T cell inhibitory molecules such as CTLA-4, PD-1, and Tim-3 are important regulators of the T cell response that have emerged as valuable immunotherapeutic targets in cancer. Among T cell inhibitory molecules, Tim-3 is now recognized as a critical determinant of the dysfunctional or exhausted CD8+ T cells that arise in cancer. Indeed, we were the first to show that expression of Tim-3 specifically marks the most dysfunctional or exhausted population of CD8+ T cells present in tumor tissue and that immunotherapy that targets Tim-3 markedly improves the efficacy of immunotherapy that targets PD-1 for restoring function to exhausted CD8+ T cells and eliciting potent anti-tumor immunity. We have now discovered that expression of Tim-3 also marks a highly suppressive population of CD4+ FoxP3+ regulatory T cells (Treg) that is uniquely present in tumor tissue. Our preliminary data further indicate that Tim-3 promotes the suppressor function of Treg. Thus, Tim-3 can impact on tumor immunity through its actions in CD8+ T cells and Treg. However, how Tim-3 may function in CD8+ T cells to dampen their responses while in Treg function to promote their suppressive activity is not known. We have now discovered that TCF-1 (T cell factor 1) is specifically down-regulated in Tim-3+ CD8+ tumor- infiltrating lymphocytes (TILs) that exhibit dysfunctional phenotype. Our preliminary data further show that blockade of Tim-3 and PD-1 signaling, which we have shown abrogates T cell exhaustion, restores expression of TCF-1 in Tim-3+ CD8+ TILs. We have further found that TCF-1 is similarly down-regulated in Tim-3+ but not Tim-3- Treg and that Tim-3/PD-1 blockade restores TCF-1 expression in Tim-3+ Treg. TCF-1 is a key transcription factor in the canonical Wnt signaling pathway. TCF-1 is required for normal T cell development and for the generation of long-lived central memory CD8+ T cells but a role for Wnt signaling and TCF-1 in the development of T cell dysfunction/exhaustion has not been addressed. Interestingly, TCF-1 has recently been implicated in antagonizing regulatory T cell function, thus raising the possibility that Tim-3-drivn repression of TCF-1 underlies the potent suppressor function of Tim-3+ Treg. Based on our preliminary data, we hypothesize that Tim-3 suppresses the anti-tumor T cell response via a mechanism that involves repression of Wnt signaling and TCF-1 in intra-tumoral CD8+ T cells and Treg. We are in a unique position to dissect the role of Tim-3 and TCF-1 in determining the anti-tumor T cell response as we have available novel tools, including Tim- 3 and TCF-1 conditional knock-out mice as well as mice that selectively express activating versus repressive forms of TCF-1 specifically in lymphocytes. We will use these newly generated tools to define the mechanisms by which Tim-3 determines anti-tumor immunity and the role of TCF-1 in this process. We propose the following specific aims: 1) Define the role of Tim-3 in CD4+FoxP3+ regulatory T cells; and 2) Define the role of Wnt signaling/TCF-1 in Tim-3-driven suppression of anti-tumor immunity.

Public Health Relevance

Cancer is a significant cause of morbidity and mortality worldwide. The immune system is capable of fighting cancer; however, the sustained expression of inhibitory receptors on anti-tumor T cells impedes the ability of the immune system to fight cancer successfully. The proposed studies will advance our knowledge of how the inhibitory receptor Tim-3 suppresses anti-tumor T cells and how immunotherapies that target Tim-3 restore productive anti-tumor immunity.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
5R01CA187975-03
Application #
9210064
Study Section
Cancer Immunopathology and Immunotherapy Study Section (CII)
Program Officer
Mccarthy, Susan A
Project Start
2015-03-01
Project End
2020-02-29
Budget Start
2017-03-01
Budget End
2018-02-28
Support Year
3
Fiscal Year
2017
Total Cost
$339,899
Indirect Cost
$134,024
Name
Brigham and Women's Hospital
Department
Type
Independent Hospitals
DUNS #
030811269
City
Boston
State
MA
Country
United States
Zip Code
02115
Singer, Meromit; Wang, Chao; Cong, Le et al. (2016) A Distinct Gene Module for Dysfunction Uncoupled from Activation in Tumor-Infiltrating T Cells. Cell 166:1500-1511.e9
Anderson, Ana C; Joller, Nicole; Kuchroo, Vijay K (2016) Lag-3, Tim-3, and TIGIT: Co-inhibitory Receptors with Specialized Functions in Immune Regulation. Immunity 44:989-1004