Li Lily Wang, PhD
Microbiology and Molecular Genetics & Cancer Center
Medical College of Wisconsin
Research Focus: Immune regulation mediated by negative checkpoint regulators; Cancer immunotherapy
PhD: Dartmouth Medical School (2003) Biochemistry
The adaptive immune response requires T cells being stimulated by antigen presenting cells (APC) that present the cognate antigens. The interaction between APC and T cells is highly regulated by a number of co-signaling molecules. Their integrated outcomes determine T cell activation, differentiation, and function (Figure 1).
Figure 1. T cell activation upon interaction with antigen presenting cells
The B7 family co-signaling molecules belongs to the Ig superfamily (Figure 2). Among them, co-stimulatory receptors, such as CD28 and ICOS, provide critical co-stimulatory signals that are required for T cell activation. On the other hand, co-inhibitory receptors, such as CTLA4, PD1, and orphan ligands such as B7H3 and B7H4, down-regulate T cell responses. These inhibitory molecules are called “immune-checkpoint regulators”. They play critical roles in maintaining peripheral tolerance, control autoimmunity, and immune responses against infection and cancer.
Figure 2. The B7 family of co-stimulatory and co-inhibitory molecules
Wang Lab discovered a novel immune-checkpoint molecule, called V-domain Immunoglobulin Suppression of T cell Activation (VISTA) (Figure 3).
Recent studies from out lab and others have established that:
- VISTA pathway directly suppresses T cell activation.
- Aged VISTAKO mice developed spontaneous T cell activation and multi-organ chronic inflammation indicating a loss of peripheral T cell tolerance.
- Young VISTAKO mice show T cell hyper-activation towards foreign antigens. Consistently, monoclonal antibody targeting VISTA enhanced endogenous or vaccine-induced anti-tumor T cell responses (Figure 4).
Figure 3. V-domain Immunoglobulin Suppressor of T cell Activation
Figure 4. VISTA-specific monoclonal antibody synergized with cancer vaccine and promoted tumor clearance in murine tumor models
We hypothesize that similar to other immune checkpoint regulators such as CTLA-4 and PD-1, VISTA critically regulates immune responses against self and foreign antigens. As such, targeting VISTA is a promising approach for treating autoimmunity, infectious disease and cancer. Our future studies will focus on addressing the following questions:
- How does VISTA regulate peripheral tolerance and autoimmunity, synergistically together with other immune-checkpoints?
- What are the molecular mechanisms of VISTA pathway, when functions as a ligand or a receptor, on various immune cell types, such as T cells and myeloid antigen present cells.
- Therapeutic development:
- How to target VISTA for cancer immunotherapy, i.e. by testing optimal combinatorial strategies, including chemotherapy, radiation, vaccine, and other co-stimulatory and co-inhibitory reagents.
- How to enhance VISTA-mediated immune suppression, for treating inflammatory diseases and autoimmune diseases.