Signals present within the tumor microenvironment (TME) undermine the ability of the immune system to fight cancer. In particular, these signals together with chronic stimulation disable effector CD8+ T cell responses by promoting the development of a dysfunctional or ?exhausted? T cell state. As dysfunctional CD8+ T cells are defective in their ability to elicit cytotoxicity and produce pro-inflammatory cytokines, they are poor mediators of tumor clearance. Moreover, dysfunctional CD8+ T cells can produce IL-10, indicating that they can also contribute to immune suppression with the TME. Thus, dysfunctional CD8+ T cells present not only an obstacle but also a liability for the generation of productive anti-tumor immunity. Accordingly, understanding both the T cell intrinsic and extrinsic signals that promote dysfunctional phenotype is of key importance in devising novel therapies to improve anti-cancer T cell responses. We have examined the gene programs underlying T cell dysfunction in CD8+ tumor-infiltrating lymphocytes (TILs). We have thus discovered that NR3C1, the gene encoding the glucocorticoid receptor (GR), is preferentially expressed by CD8+ TILs that exhibit severe dysfunctional phenotype. Glucocorticoids (GCs) are steroid hormones and ligands for GR. Although both natural and synthetic glucocorticoids are known to be potent immune-suppressive agents, the precise molecular mechanisms by which they suppress effector T cell responses are poorly understood. Our preliminary data indicate that GC-GR signaling is indeed active in CD8+ TILs and that tumor-associated macrophages (TAMs) are a local source of steroid in the TME. We further find that mice that lack expression of NR3C1 specifically in CD8+ T cells exhibit improved tumor growth control and that NR3C1-deficient CD8+ TILs exhibit improved effector function concomitant with dramatically reduced expression of co-inhibitory receptors such as Tim-3 and PD-1. In line with these data, we find that GC-GR signaling promotes co-inhibitory receptor expression and dampens both the cytotoxic capacity and pro-inflammatory cytokine production of CD8+ T cells in vitro. Interestingly, we find that GC-GR signaling potently synergizes with the immunoregulatory cytokine IL-27 to further augment the expression of co-inhibitory receptors and dampen pro-inflammatory cytokine production and cytotoxic capacity in CD8+ T cells while concomitantly inducing IL-10 production. Based on our preliminary data, we hypothesize that GC-GR signaling is a key component of the immune suppressive network in the TME that disables anti-tumor T cell responses by: 1) direct promotion of dysfunction-associated gene programs in effector T cells; and 2) synergizing with signals in the TME such as IL-27. We propose the following specific aims: 1) Molecularly dissect the role of steroid signaling in CD8+ and CD4+ T cells in the TME and 2) Define the GC-GR signaling circuit and the basis for synergy with IL-27 in immune- suppression in the TME.
Cancer is a significant cause of morbidity and mortality worldwide. The immune system is capable of fighting cancer; however, suppressive mechanisms present in tumors impede the ability of the immune system to fight cancer successfully. The proposed studies will advance our knowledge of how steroid hormone signaling operates in tumor tissue to suppress anti-tumor immune responses.