Immunotherapy has quickly become a first line treatment option in both melanoma and non-small cell lung cancer thanks in large part to the clinical success of neutralizing antibodies directed at programmed death receptor 1 (PD-1). PD-1 functions primarily on T cells as a method of peripheral immune tolerance. However, in a cancerous setting, tumors or various cells with in the tumor microenvironment can upregulate the ligand for PD-1, PD-L1 or PD-L2. The ensuing interaction between the receptor and ligand causes T cells, which may be specific for the tumor, to become dysfunctional allowing for cancer progression. Pharmacological inhibition of the PD-1/PD-L1 axis can restore T cell functionality resulting in meaningful therapeutic responses. However, this benefit is not uniform with long lasting response rates seen in only a fraction of patients. A possible explanation for this dichotomy could be the presence of other immunosuppressive factors within the tumor microenvironment which function independently of the PD-1/PD-L1 axis. As the breadth of ?PD-1 treatments spread across cancer types, there is an urgent need to understand the underlying mechanisms responsible for the varied response rates. Preliminary data from our lab found that platelets suppress T cell activity in vitro and in vivo, resulting in diminished tumor control. Although TGF-?1 played a predominant role in the in vitro suppression, conditional knockout of the cytokine specifically from the platelet compartment alone was not sufficient to enhance T cell mediated tumor control. Deletion of soluble TGF-?1 from platelets had no effect on platelet expression of GARP, the membrane docking receptor for TGF-?. GARP has been shown to mediate immune suppression by controlling the bioavailability and activation of TGF-?1. Serum analysis across several conditional knockout mice found that deletion of GARP but not soluble TGF-?1 from platelets resulted in lower concentrations of biologically active TGF-?1. Furthermore, we found that GARP expression was increased on platelets following activation in vitro. Given these preliminary results, our central hypothesis is that platelets negatively regulate the antitumor T cell response by controlling the bioavailability of TGF-?1 within the tumor microenvironment following activation. We will address this hypothesis through a set of specific aims.
In Aim 1, we will identify the mechanism of platelet mediated T cell suppression. Our working hypothesis here is following activation, platelets suppress T cell functionality specifically through the GARP/TGF-?1 axis.
In Aim 2, we will Determine whether combination antiplatelet therapy and ?PD-1 improves tumor specific T cell functionality. Our working hypothesis is that platelet mediated suppression is mechanistically distinct from that of the PD-1/PD-L1 interaction. Therefore, by targeting platelet activation in concert with ?PD-1 will improve the T cell response to cancer.
Immunotherapy has quickly become a first line treatment option in both melanoma and non-small cell lung cancer thanks in large part to the clinical success of neutralizing antibodies directed at programmed death receptor 1 (PD-1). However, this benefit is not uniform with long lasting response rates seen in only a fraction of patients. Therefore, as the breadth of ?PD-1 treatments spread across cancer types, there is an urgent need to understand the underlying mechanisms responsible for the varied response rates.
