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Tumour-specific CD8 T cell dysfunction is a differentiation state that is distinct from the functional effector or memory T cell states.sup.1-6. Here we identify the nuclear factor TOX as a crucial regulator of the differentiation of tumour-specific T (TST) cells. We show that TOX is highly expressed in dysfunctional TST cells from tumours and in exhausted T cells during chronic viral infection. Expression of TOX is driven by chronic T cell receptor stimulation and NFAT activation. Ectopic expression of TOX in effector T cells in vitro induced a transcriptional program associated with T cell exhaustion. Conversely, deletion of Tox in TST cells in tumours abrogated the exhaustion program: Tox-deleted TST cells did not upregulate genes for inhibitory receptors (such as Pdcd1, Entpd1, Havcr2, Cd244 and Tigit), the chromatin of which remained largely inaccessible, and retained high expression of transcription factors such as TCF-1. Despite their normal, 'non-exhausted' immunophenotype, Tox-deleted TST cells remained dysfunctional, which suggests that the regulation of expression of inhibitory receptors is uncoupled from the loss of effector function. Notably, although Tox-deleted CD8 T cells differentiated normally to effector and memory states in response to acute infection, Tox-deleted TST cells failed to persist in tumours. We hypothesize that the TOX-induced exhaustion program serves to prevent the overstimulation of T cells and activation-induced cell death in settings of chronic antigen stimulation such as cancer. The nuclear factor TOX is highly expressed in antigen-specific dysfunctional T cells in tumours and exhausted T cells during chronic viral infection and is a crucial regulator of the differentiation of tumour-specific T cells., Author(s): Andrew C. Scott [sup.1] [sup.2] , Friederike Dündar [sup.3] [sup.4] , Paul Zumbo [sup.3] [sup.4] , Smita S. Chandran [sup.5] [sup.6] , Christopher A. Klebanoff [sup.5] [sup.6] [sup.7] [sup.8] [...]

Chimeric antigen receptors (CARs) are synthetic antigen receptors that reprogram T cell specificity, function and persistence.sup.1. Patient-derived CAR T cells have demonstrated remarkable efficacy against a range of B-cell malignancies.sup.1-3, and the results of early clinical trials suggest activity in multiple myeloma.sup.4. Despite high complete response rates, relapses occur in a large fraction of patients; some of these are antigen-negative and others are antigen-low.sup.1,2,4-9. Unlike the mechanisms that result in complete and permanent antigen loss.sup.6,8,9, those that lead to escape of antigen-low tumours remain unclear. Here, using mouse models of leukaemia, we show that CARs provoke reversible antigen loss through trogocytosis, an active process in which the target antigen is transferred to T cells, thereby decreasing target density on tumour cells and abating T cell activity by promoting fratricide T cell killing and T cell exhaustion. These mechanisms affect both CD28- and 4-1BB-based CARs, albeit differentially, depending on antigen density. These dynamic features can be offset by cooperative killing and combinatorial targeting to augment tumour responses to immunotherapy. Chimeric antigen receptors (CARs) promote antigen loss in tumour cells by trogocytosis, which results in T cell fratricide killing and exhaustion but can be counteracted by cooperative killing and combinatorial targeting., Author(s): Mohamad Hamieh [sup.1] , Anton Dobrin [sup.1] , Annalisa Cabriolu [sup.1] , Sjoukje J. C. van der Stegen [sup.1] , Theodoros Giavridis [sup.1] , Jorge Mansilla-Soto [sup.1] , Justin [...]

Dysfunctional T cells in the tumour microenvironment have abnormally high expression of PD-1 and antibody inhibitors against PD-1 or its ligand (PD-L1) have become commonly used drugs to treat various types of cancer.sup.1-4. The clinical success of these inhibitors highlights the need to study the mechanisms by which PD-1 is regulated. Here we report a mechanism of PD-1 degradation and the importance of this mechanism in anti-tumour immunity in preclinical models. We show that surface PD-1 undergoes internalization, subsequent ubiquitination and proteasome degradation in activated T cells. FBXO38 is an E3 ligase of PD-1 that mediates Lys48-linked poly-ubiquitination and subsequent proteasome degradation. Conditional knockout of Fbxo38 in T cells did not affect T cell receptor and CD28 signalling, but led to faster tumour progression in mice owing to higher levels of PD-1 in tumour-infiltrating T cells. Anti-PD-1 therapy normalized the effect of FBXO38 deficiency on tumour growth in mice, which suggests that PD-1 is the primary target of FBXO38 in T cells. In human tumour tissues and a mouse cancer model, transcriptional levels of FBXO38 and Fbxo38, respectively, were downregulated in tumour-infiltrating T cells. However, IL-2 therapy rescued Fbxo38 transcription and therefore downregulated PD-1 levels in PD-1.sup.+ T cells in mice. These data indicate that FBXO38 regulates PD-1 expression and highlight an alternative method to block the PD-1 pathway.PD-1 undergoes internalization, FBXO38-mediated ubiquitination and proteasome degradation in activated T cells, and inhibition of this pathway dampens anti-tumour immunity of T cells., Author(s): Xiangbo Meng [sup.1] , Xiwei Liu [sup.1] , Xingdong Guo [sup.1] , Shutan Jiang [sup.1] , Tingting Chen [sup.2] , Zhiqiang Hu [sup.3] [sup.4] , Haifeng Liu [sup.5] , [...]

Acetylation of histones by lysine acetyltransferases (KATs) is essential for chromatin organization and function.sup.1. Among the genes coding for the MYST family of KATs (KAT5-KAT8) are the oncogenes KAT6A (also known as MOZ) and KAT6B (also known as MORF and QKF).sup.2,3. KAT6A has essential roles in normal haematopoietic stem cells.sup.4-6 and is the target of recurrent chromosomal translocations, causing acute myeloid leukaemia.sup.7,8. Similarly, chromosomal translocations in KAT6B have been identified in diverse cancers.sup.8. KAT6A suppresses cellular senescence through the regulation of suppressors of the CDKN2A locus.sup.9,10, a function that requires its KAT activity.sup.10. Loss of one allele of KAT6A extends the median survival of mice with MYC-induced lymphoma from 105 to 413 days.sup.11. These findings suggest that inhibition of KAT6A and KAT6B may provide a therapeutic benefit in cancer. Here we present highly potent, selective inhibitors of KAT6A and KAT6B, denoted WM-8014 and WM-1119. Biochemical and structural studies demonstrate that these compounds are reversible competitors of acetyl coenzyme A and inhibit MYST-catalysed histone acetylation. WM-8014 and WM-1119 induce cell cycle exit and cellular senescence without causing DNA damage. Senescence is INK4A/ARF-dependent and is accompanied by changes in gene expression that are typical of loss of KAT6A function. WM-8014 potentiates oncogene-induced senescence in vitro and in a zebrafish model of hepatocellular carcinoma. WM-1119, which has increased bioavailability, arrests the progression of lymphoma in mice. We anticipate that this class of inhibitors will help to accelerate the development of therapeutics that target gene transcription regulated by histone acetylation.Selective inhibitors of KAT6A and KAT6B inhibit MYST-catalysed histone acetylation, induce cell cycle exit and cellular senescence without causing DNA damage, and arrest lymphoma progression in mouse models., Author(s): Jonathan B. Baell [sup.1] [sup.2] , David J. Leaver [sup.1] , Stefan J. Hermans [sup.3] , Gemma L. Kelly [sup.4] [sup.5] , Margs S. Brennan [sup.4] [sup.5] , Natalie [...]