Cancer immunotherapy and autoimmunity in mice lacking checkpoint inhibitors

Project Description: The progression of a productive immune response requires that a number of immunological checkpoints be passed. Passage may require the presence of excitatory co-stimulatory signals or the avoidance of negative or co-inhibitory signals, which act to dampen or terminate immune activity. The immunoglobulin superfamily occupies a central importance in this coordination of immune responses, and the CD28/cytotoxic T-lymphocyte antigen-4 (CTLA-4):B7.1/B7.2 receptor/ligand grouping represents the archetypal example of these immune regulators. In part, the role of these checkpoints is to guard against the possibility of unwanted and harmful self-directed activities. While this is a necessary function, aiding in the prevention of autoimmunity, it may act as a barrier to successful immunotherapies aimed at targeting malignant self-cells that largely display the same array of surface molecules as the cells from which they derive. Therapies aimed at overcoming these mechanisms of peripheral tolerance, in particular by blocking the inhibitory checkpoints on T cells, offer the potential to generate anti-cancer activity, either as monotherapies or in synergism with other therapies that directly or indirectly enhance presentation of tumor epitopes to the immune system. Such anti-lymphocyte checkpoint antibodies are showing promise in early clinical trials of advanced human cancers. An emerging group of immunoglobulin superfamily members that interact with ligands of the nectin and nectin-like (necl) family has recently been described to influence NK cell and T cell functions. These include CD226 (DNAM-1), CD96 (TACTILE), TIGIT (T cell immunoglobulin and ITIM domain), and CRTAM (class I restricted T cell-associated molecule).

Despite being cloned 20 years ago, little is known about CD96, the other immunoglobulin family member that shares CD155 ligand with DNAM-1 and TIGIT. In humans, CD96 expression is largely confined to NK cells, CD8 T cells, and CD4 T cells. The major ligand of CD96 is CD155, but CD96 has also been reported to associate with CD111 (nectin-1) and play a role in promoting NK cell and T cell adhesion. In a recent study we have demonstrated that CD96 competes with DNAM-1 for CD155 binding and limits NK cell functions by direct inhibition. As a result, CD96-/- mice displayed hyper-inflammatory responses to bacterial product LPS and a resistance to tumor metastases. These data provided the first description of the ability of CD96 to negatively control cytokine responses by lymphocytes. Thus, blocking CD96 may have applications in pathologies where NK and T cells play an important role.

Now we wish to evaluate anti-CD96 monoclonal antibody in mice as a novel cancer immunotherapy, alone and in the context of conventional therapies such as surgery, targeted therapies (Her2/neu), chemotherapy, and checkpoint blockade (CTLA-4 or PD-1). We will examine experimental and spontaneous tumor metastases models and established transplanted and de novo primary tumors. We will also evaluate tumor immunity and autoimmunity in mice in the absence of CD96, TIGIT and PD-1. In humans we will evaluate the ability of anti-human CD96 monoclonal antibodies to rescue lymphocyte function. The candidate will learn a huge range of cellular immunology techniques, cancer biology/models and state-of-the art flow cytometry.

http://www.qimrberghofer.edu.au/page/Lab/Immunology_Cancer_Infection/