Towards Small Molecule Therapies to Reverse T Cell Exhaustion

T cells of the adaptive immune system are a vital part of the defense against pathogens and cancers. T cells are not invulnerable, unfortunately. T cell exhaustion is a feature of cancers, persistent viral infections, and aging. Exhausted T cells are characterized by inhibition of replication, reduced secretion of immune signals, and sharply limited activity. The proximate cause is of this state is the expression of immune checkpoint proteins such as PD-1. The cancer research industry has achieved considerable success in the development of checkpoint inhibitors, monoclonal antibodies that bind to and inhibit immune checkpoint proteins. These therapies can effectively reverse T cell exhaustion in the context of cancer, allowing the immune system to more effectively attack tumor cells.

Are there other options? Today's open access paper reports on the development of a screening system to allow a search for small molecules capable of reversing T cell exhaustion. This is again achieved by interfering with the operation of immune checkpoints or their immediately downstream biochemistry. Small molecule therapies might be more appropriate than monoclonal antibodies for the reduction of T cell exhaustion in chronic viral infection or in older people in general, particularly given the relative costs of these two approaches.

Discovery of Small Molecules for the Reversal of T Cell Exhaustion

Immune surveillance for the recognition and removal of unwanted virus infected cells and the detection and attack of malignant cells resides primarily with the activity of cytotoxic T lymphocytes (CTLs). To counteract this response, viruses, and cancers reduce the function of CTLs, exhausting them. This is achieved, in part, by upregulation of inhibitory "checkpoint" receptors (IRs) on the surfaces of CTLs. The importance of this strategy in controlling T cell responses is illuminated by findings that neutralizing IRs such as PD-1 or CTLA-4 on exhausted T cells restores their effector responses. The use of such checkpoint inhibitory therapies has led to remarkable clinical benefits in cancer patients.

However, responses in many patients remain limited, in part, due to insufficient restoration of T cell function. Thus, the discovery of additional targets and pharmacologic drugs is required to overcome the limitations of current checkpoint blockade. Therapeutics with distinct properties could enhance the effectiveness of existing IR blockade agents or achieve responses in patients resistant to existing treatment modalities. Several recent reports examining the synergistic effects of antibody-based blockade strategies by targeting alternative IRs, cytokines, or cytokine signaling pathways have sparked numerous clinical trials. Discovery and utilization of low-molecular-weight therapeutics can complement, and in some cases replace, existing IR blockade biologics.

Functional exhaustion of virus-specific T cells was first described in mice infected with the clone 13 (CL13) variant of lymphocytic choriomeningitis virus (LCMV). CL13 causes a persistent viral infection resulting in varying degrees of suboptimal CD4 and CD8 T cell activity, characterized by reduced to absent cytotoxic capacity of anti-viral CD8 T cells, poor proliferative potential, decreased production of antiviral effector molecules such as interferon γ (IFN-γ) and tumor necrosis factor α (TNF-α), insufficient expression of several homeostatic cytokines, and sustained expression of IRs such as PD-1, LAG-3, and TIM-3 and the immunosuppressive cytokine interleukin-10 (IL-10). T cell exhaustion is progressive and thought to be driven by persistent antigen stimulation. The importance of immunosuppressive pathways that maintain T cell dysfunction was initially demonstrated by the resurrection of T cell activity following PD-1 or IL-10 receptor blockade during persistent LCMV infection.

Here, we report utilizing the in vivo LCMV-CL13 model to construct a platform for in vitro high-throughput screening (HTS) to detect small molecules that reverse T cell exhaustion. We identify 19 compounds from the ReFRAME drug-repurposing collection that restore cytokine production and enhance the proliferation of exhausted T cells. Analysis of our top hit, ingenol mebutate, a protein kinase C (PKC) inducing diterpene ester, reveals a role for this molecule in overriding the suppressive signaling cascade mediated by IR signaling on T cells. Collectively, these results demonstrate a disease-relevant methodology for identifying modulators of T cell function and reveal new targets for immunotherapy.

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