Grabbing all gene lists in which at least three of the markers were perturbed gave us 307 lists. Retaining the markers, we generated a frequency table of genes most commonly found in these lists. The markers lag3, pd-1, and tim3 topped the list. The fourth most frequent gene in our list was not one of the 7 markers: gzmb. After ctla4 and tigit we have ccl5, cst7, ccl4, gzma, and ccl3. Cd244 and cd160 occupied the 21st and 27th positions on the list. Our final list of genes associated with t-cell exhaustion contains 188 genes, with all genes required to be found at least 60 times over the 307 lists.
Presumably, we'd like to downregulate these genes aggressively in cancer, allowing the immune system and immunotherapies to go to work. Sticking with known drug/treatment regimens (as opposed to, say, knockouts which may be difficult to implement for the time being) in lymphocytes, the single best treatment would be the presence (versus absence) of zinc in mouse drinking water: Interleukin-10 induces interferon-γ-dependent emergency myelopoiesis. Next is a dca (16-didehydro-cortistatin A) regimen: The Cyclin-Dependent Kinase 8 (CDK8) Inhibitor DCA Promotes a Tolerogenic Chemical Immunophenotype in CD4+ T Cells via a Novel CDK8-GATA3-FOXP3 Pathway. This is followed by mouse studies involving leukocyte costimulatory blockade antibody treatment, Short-term Immunosuppression Promotes Engraftment of Embryonic and Induced Pluripotent Stem Cells, and NAC treatment, Impaired mitochondrial oxidative phosphorylation limits the self-renewal of T cells exposed to persistent antigen. A mouse study involving ricolinostat, an hdac6 inhibitor, follows, but we note that this drug also upregulated a significant number of genes in our t-cell exhaustion list. Such is biology.
The first human study wherein a treatment downregulates genes in the t-cell exhaustion list is this: TNFR2 Costimulation Differentially Impacts Regulatory and Conventional CD4+ T-Cell Metabolism. The study involves application of a tnfr2 agonist antibody to cd4 t-cells. The next human study involves treatment with a cd45 fragment: The soluble cytoplasmic tail of CD45 (ct‐CD45) in human plasma contributes to keep T cells in a quiescent state.
Ignoring solutions that might be relatively practical in 2024, we see a study in which a foxp3 k18r mutation results in exhaustion gene downregulation (Foxp3 Reprograms T Cell Metabolism to Function in Low-Glucose, High-Lactate Environments), followed by the aforementioned map4k1 ko, batf3 oe, tbx21 ko, tak1 ko, tfam ko, regnase-1 ko, rbx1 ko, and en2 ko.
In terms of disease-related studies, we see these exhaustion genes downregulated in responding vs non-responding leukemia patients in Reversal of in situ T-cell exhaustion during effective human antileukemia responses to donor lymphocyte infusion. This is not surprising, but it's nice to see validation of the standard dogma regarding t-cell exhaustion. Then again, the next disease study on the list might surprise: In Single-cell landscape of the ecosystem in early-relapse hepatocellular carcinoma, t-cells associated with relapse tended to be depleted of exhaustion genes. Upregulated exhaustion genes were not only seen in cancers: see lymphocytic genes in Metallothioneins as dynamic markers for brain disease in lysosomal disorders and Hypomethylation and Overexpression of Th17-Associated Genes is a Hallmark of Intestinal CD4+ Lymphocytes in Crohn's Disease. HIV progression vs control is associated with upregulation of exhaustion genes in Transcriptional analysis of HIV-specific CD8+ T cells shows that PD-1 inhibits T cell function by upregulating BATF. In DUSP4-mediated accelerated T-cell senescence in idiopathic CD4 lymphopenia, mouse t-regs show an upregulated exhaustion signature in the diseased state.
Unfortunately, there aren't any "DIY" sorts of treatments that downregulate exhaustion genes with high significance (we set P = 10^-15 as a cutoff). Zinc supplementation is interesting, but we wish the study were conducted in humans. We will upload the exhaustion list to our database in the next week or two and post the database ID just below when we do. Then you can search for all treatments, diseases, knockouts, etc. that up- or down-regulate the exhaustion signature. It is possible that strong alteration of the exhaustion signature could be accomplished with a cocktail of treatments, each without astounding efficacy alone; to test such hypothesise, be sure to check out our "Third Set" tool to examine this possibility.
