The role of PD-1 in modulating T cell responses in autoimmunity and cancer

Abstract

With the emergence of PD-1 blockade as a promising therapeutic for cancer treatment, a better understanding of immune-related adverse events associated with checkpoint blockade therapy and the role of PD-1 in maintaining tolerance is needed. In this thesis, I investigated the role of PD-1 in regulating cancer, autoimmunity and peripheral tolerance by undertaking three independent studies. First, I examined the role of PD-1 selectively on CD4+ Foxp3+ regulatory (Treg) T cells by generating conditional knock-out mice that deleted PD-1 only in Treg cells. I observed increased suppressive capacity of PD-1-/- Treg cells both in vivo and in vitro, due in part to reduced PI3K-AKT signaling. Using a combination of functional and transcriptomic studies, I determined that cell-intrinsic inhibition of Treg cells is a significant mechanism by which PD-1 regulates tolerance and autoimmunity. Secondly, to better understand the mechanism by which PD-1 mediates cell-intrinsic T cell inhibition, I studied two mouse strains in which the tyrosine residues in two known downstream signaling motifs, ITIM and ITSM, were mutated. While ITIM mutant mice were similar to wild-type, ITSM mutant mice showed superior tumor growth control and increased survival, similar to PD-1-/- mice. This phenotype was attributed to better CD8+ T cell effector function. ITSM mutant mice, however, did not display the increased severity of autoimmune disease associated with PD-1 loss. In vitro studies and adoptive transfer experiments suggested that ITSM Treg cells are better able to suppress effector cell-mediated inflammation in autoimmune disease compared to PD-1-/- Treg cells. Finally, I studied the effect of co-blockade of PD-1 and TIGIT and observed that loss of both receptors enhanced tumor growth control but did not increase autoimmunity. This phenotype may be Treg-mediated, as Treg cells with loss of both receptors exhibited enhanced, rather than diminished, suppressive function. Our findings highlight TIGIT as a possible partner for co- blockade with PD-1. Thus, using a combination of mouse models, in vitro assays and transcriptomic approaches, I have identified mechanisms of PD-1-mediated tolerance related to regulatory T cells and discovered two novel methods for uncoupling beneficial effects of PD-1 blockade in tumor immunity from development of autoimmunity.