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Neural stem cells (NSCs) are the source of new neurons, astrocytes, and oligodendrocytes in the adult mammalian brain. Studies in rodents show that adult-born neurons contribute to learning and memory, sensory functions, and mood regulation (Bond et al., 2015).NSCs are located in distinct niches in the subventricular zone (SVZ) of the lateral ventricle and the dentate gyrus of the hippocampus that provide molecular cues for cell proliferation and differentiation. Similar to rodents and non-human primates, NSCs undergo

20Adult neural stem cells are largely quiescent, and require transcriptional reprogramming 21 to reenter the cell cycle and undergo neurogenesis. However, the precise mechanisms 22 that underlie the rapid transcriptional overhaul during NSC activation remain undefined. 23Here, we identify the genome-wide chromatin accessibility differences between primary 24 neural stem and progenitor cells in quiescent and activated states. We show that these 25 distinct cellular states exhibit both shared and unique chromatin profiles, which are both 26 associated with gene regulation. Interestingly, we find that accessible chromatin states 27 specific to quiescent or activated cells are active enhancers bound by pro-neurogenic 28 and quiescence factors, ASCL1 and NFI. In contrast, shared sites are gene promoters 29 harboring constitutively accessible chromatin enriched for particular core promoter 30 elements that are functionally associated with translation and metabolic functions. 31Together, our findings reveal how accessible chromatin states regulate a transcriptional 32 overhaul and drive the switch between quiescence and proliferation in NSC activation. 33 34 46In vivo, the majority of NSCs reside in a state of quiescence 10 . Quiescent NSCs (qNSCs) 47 have exited the cell cycle but can be prompted by intrinsic or extrinsic cues to "activate" 48 and re-enter the cell cycle (we refer to these cells as activated NSCs, or aNSCs). Once 49 activated, aNSCs proliferate and may return to quiescence and self-renew, or 50 differentiate into neurons or glia. Activation of qNSCs is the first critical step in 51 neurogenesis in the adult brain, and is enhanced in response to damage (e.g. stroke) or 52 environmental stimuli such as parabiosis [11][12][13] . Evidence shows that decreased 53 neurogenesis with age occurs due to reduced activation of qNSCs, senescence of the 54 NSC niche, and exhaustion of the qNSC pool [14][15][16][17] . Accumulation of qNSCs has also been 55 observed in a rodent model for neurodevelopmental disorders, suggesting that a careful 56 balance of NSC quiescence and activation is necessary for healthy cognitive function 18 . 57However, the precise mechanisms that regulate this balance and prompt qNSCs to re-58 enter the cell cycle in the healthy mammalian brain are mostly unknown. 59 60 Recent studies reported that quiescent and activated NSCs employ cell type-specific 61 mechanisms to support their functionality, including distinct metabolic states and 62 differences in proteostasis [19][20][21] . Transcriptional profiling of qNSCs and aNSCs revealed 63 both shared and distinct transcriptional signatures in the two cell types, indicating that a 64 transcriptional overhaul occurs at a subset of genes during the process of NSC 65 activation 10,19,22,23 . For example, genes involved in cell proliferation, lipid metabolism, and 66 protein homeostasis were differentially expressed in quiescent and activated NSCs. 67 Similar changes have also been observed using in vitro models of NSC quiescence and 68 activation...

Immune checkpoint blockade is effective for a subset of patients across many cancers, but most patients are refractory to current immunotherapies and new approaches are needed to overcome resistance. The protein tyrosine phosphatase PTPN2 is a central regulator of inflammation, and genetic deletion of PTPN2 on either tumor cells or host immune cells promotes anti-tumor immunity. However, inhibitors of PTPN2 have not been described. Here, we present the validation of ABBV-CLS-484, a potent catalytic inhibitor of PTPN2 and the closely related phosphatase PTPN1. ABBV-CLS-484 treatment of tumor cells in vitro phenocopies the genetic deletion of PTPN2/N1, causing both amplified transcriptional responses to IFNg and reduced cell viability across human cancer cell lines. Monotherapy ABBV-CLS-484 treatment generates robust anti-tumor immunity in several murine cancer models with efficacy comparable to anti-PD-1 treatment. Through genetic studies, we show that while ABBV-CLS-484 can act on both tumor cells and the host immune system, IFN sensing and PTPN2/N1 expression on tumor cells are not always required for efficacy, suggesting that PTPN2/N1 inhibition on host immune cells may be sufficient for activity of the drug. Through scRNAseq profiling of TILs from both ABBV-CLS-484-treated and anti-PD-1-treated tumors, we show that ABBV-CLS-484 induces unique transcriptional changes to both myeloid and lymphoid populations in the tumor microenvironment which are dominated by enhanced IFN sensing and a shift from suppressive to pro-inflammatory phenotypes. ABBV-CLS-484 treatment enhances the activation and effector functions of CD8+ T cells while decreasing the expression of genes classically associated with T cell exhaustion and dysfunction such as Tox. The efficacy of ABBV-CLS-484 is critically dependent on CD8+ T cells and treatment with ABBV-CLS-484 results in greater levels of T cell infiltration into tumors and a more diverse repertoire of expanded T cell clones relative to anti-PD-1. Thus, the PTPN2/N1 inhibitor ABBV-CLS-484 is a highly effective immunotherapy with monotherapy efficacy across mouse tumor models. Small molecule inhibitors of PTPN2 offer a promising new strategy for cancer immunotherapy by targeting an IFN signaling checkpoint and are currently being evaluated clinically in patients with advanced solid tumors (NCT04777994). Citation Format: Arvin Iracheta-Vellve, Hakimeh Ebrahimi-Nik, Thomas R. Davis, Kira E. Olander, Sarah Y. Kim, Mitchell D. Yeary, James C. Patti, Ian C. Kohnle, Christina K. Baumgartner, Keith M. Hamel, Kathleen A. McGuire, Cun Lan Chuong, Zhaoming Xiong, Elliot P. Farney, Jennifer M. Frost, Matthew Rees, Andrew Boghossian, Melissa Ronan, Jennifer A. Roth, Todd R. Golub, Gabriel K. Griffin, Clay Beauregard, Philip R. Kym, Kathleen B. Yates, Robert T. Manguso. Targeting the immune checkpoint PTPN2 with ABBV-CLS-484 inflames the tumor microenvironment and unleashes potent CD8+ T cell immunity [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 606.