Immune checkpoint blockade against programmed cell death 1 (PD-1) and its ligand PD-L1 often induces durable tumor responses in various cancers, including non-small cell lung cancer (NSCLC). However, ...therapeutic resistance is increasingly observed, and the mechanisms underlying anti-PD-L1 (aPD-L1) antibody treatment have not been clarified yet. Here, we identified two unique secreted PD-L1 splicing variants, which lacked the transmembrane domain, from aPD-L1-resistant NSCLC patients. These secreted PD-L1 variants worked as "decoys" of aPD-L1 antibody in the HLA-matched coculture system of iPSC-derived CD8 T cells and cancer cells. Importantly, mixing only 1% MC38 cells with secreted PD-L1 variants and 99% of cells that expressed wild-type PD-L1 induced resistance to PD-L1 blockade in the MC38 syngeneic xenograft model. Moreover, anti-PD-1 (aPD-1) antibody treatment overcame the resistance mediated by the secreted PD-L1 variants. Collectively, our results elucidated a novel resistant mechanism of PD-L1 blockade antibody mediated by secreted PD-L1 variants.
Abstract
In currently ongoing adoptive T-cell therapies, T cells collected from the patient are given back to the patient after ex vivo cell activation and expansion. In some cases, T cells are ...transduced with chimeric antigen receptor (CAR) or T-cell receptor (TCR) genes during the ex vivo culture period. Although such strategies have been shown to be effective in some types of cancer, there remain issues to be solved; these methods (i) are time-consuming, (ii) are costly and (iii) it is difficult to guarantee the quality because the products depend on patient-derived T cells. To address these issues, several groups including ours have developed methods in which cytotoxic cells are mass-produced by using induced pluripotent stem cell (iPSC) technology. For the regeneration of T cells, the basic idea is as follows: iPSCs produced from T cells inherit rearranged TCR genes, and thus all regenerated T cells should express the same TCR. Based on this idea, various types of T cells have been regenerated, including conventional cytotoxic T lymphocytes (CTLs), γδT cells, NKT cells and mucosal-associated invariant T (MAIT) cells. On the other hand, any cytotoxic cells can be used as the base cells into which CAR is introduced, and thus iPSC-derived NK cells have been developed. To apply the iPSC-based cell therapy in an allogeneic setting, the authors’ group developed a method in which non-T-cell-derived iPSCs are transduced with exogenous TCR genes (TCR-iPSC method). This approach is being prepared for a clinical trial to be realized in Kyoto University Hospital, in which acute myeloid leukemia patients will be treated by the regenerated WT1 antigen-specific CTLs.
Graphical Abstract
Graphical Abstract
Cells forming malignant tumors are distinguished from those forming normal tissues based on several features: accelerated/dysregulated cell division, disruption of physiologic apoptosis, ...maturation/differentiation arrest, loss of polarity, and invasive potential. Among them, accelerated cell division and differentiation arrest make tumor cells similar to stem/progenitor cells, and this is why tumorigenesis is often regarded as developmental reversion. Here, in addition to developmental reversion, we propose another insight into tumorigenesis from a phylogeny viewpoint. Based on the finding that tumor cells also share some features with unicellular organisms, we propose that tumorigenesis can be regarded as “evolutionary reversion”. Recent advances in sequencing technologies and the ability to identify gene homologous have made it possible to perform comprehensive cross-species transcriptome comparisons and, in our recent study, we found that leukemic cells resulting from a polycomb dysfunction transcriptionally resemble unicellular organisms. Analyzing tumorigenesis from the viewpoint of phylogeny should reveal new aspects of tumorigenesis in the near future, and contribute to overcoming malignant tumors by developing new therapies.
Summary
SgrS is an Hfq‐binding small antisense RNA that is induced upon phosphosugar stress. It forms a ribonucleoprotein complex with RNase E through Hfq to mediate silencing of the target ptsG mRNA ...encoding the membrane component of the glucose‐specific phosphoenolpyruvate phosphotransferase system. Although SgrS is believed to act on ptsG mRNA through base pairing between complementary regions, this was not previously tested experimentally. We addressed the question of whether SgrS indeed forms an RNA–RNA duplex with ptsG mRNA to exert its regulatory function. Specific single nucleotide substitutions around the Shine–Dalgarno (SD) sequence of ptsG completely eliminated SgrS action while compensatory mutations in SgrS restored it. A systematic mutational analysis of both ptsG and SgrS RNAs revealed that six base pairs around SD sequence of ptsG are particularly important for SgrS action. We also showed in vitro that SgrS forms a stable duplex with the ptsG mRNA, and that Hfq markedly facilitates the rate of duplex formation.
The concept that blood cells arising from hematopoietic stem cells (HSC) can be subdivided into two major lineages, a myelo-erythroid and a lymphoid lineage, has long persisted. Indeed, it has become ...almost axiomatic that the first branch point from the HSC produces two progenitors, one for myelo-erythroid cells and the other for lymphoid cells. However, recent studies have provided a battery of findings that cannot be explained by this classical model. We will outline how this classical model arose before describing how we came to propose an alternative ‘myeloid-based model’, in which myeloid potential is retained in erythroid, T, and B cell branches even after these lineages have segregated from each other.
There is heterogeneity in invariant natural killer T (iNKT) cells based on the expression of CD4 and the IL-17 receptor B (IL-17RB), a receptor for IL-25 which is a key factor in T(H)2 immunity. ...However, the development pathway and precise function of these iNKT cell subtypes remain unknown. IL-17RB⁺iNKT cells are present in the thymic CD44⁺/⁻ NK1.1⁻ population and develop normally even in the absence of IL-15, which is required for maturation and homeostasis of IL-17RB⁻iNKT cells producing IFN-γ. These results suggest that iNKT cells contain at least two subtypes, IL-17RB⁺ and IL-17RB⁻ subsets. The IL-17RB⁺iNKT subtypes can be further divided into two subtypes on the basis of CD4 expression both in the thymus and in the periphery. CD4⁺ IL-17RB⁺iNKT cells produce T(H)2 (IL-13), T(H)9 (IL-9 and IL-10), and T(H)17 (IL-17A and IL-22) cytokines in response to IL-25 in an E4BP4-dependent fashion, whereas CD4⁻ IL-17RB⁺iNKT cells are a retinoic acid receptor-related orphan receptor (ROR)γt⁺ subset producing T(H)17 cytokines upon stimulation with IL-23 in an E4BP4-independent fashion. These IL-17RB⁺iNKT cell subtypes are abundantly present in the lung in the steady state and mediate the pathogenesis in virus-induced airway hyperreactivity (AHR). In this study we demonstrated that the IL-17RB⁺iNKT cell subsets develop distinct from classical iNKT cell developmental stages in the thymus and play important roles in the pathogenesis of airway diseases.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Innate and adaptive lymphoid development is orchestrated by the activities of E proteins and their antagonist Id proteins, but how these factors regulate early T cell progenitor (ETP) and innate ...lymphoid cell (ILC) development remains unclear. Using multiple genetic strategies, we demonstrated that E proteins E2A and HEB acted in synergy in the thymus to establish T cell identity and to suppress the aberrant development of ILCs, including ILC2s and lymphoid-tissue-inducer-like cells. E2A and HEB orchestrated T cell fate and suppressed the ILC transcription signature by activating the expression of genes associated with Notch receptors, T cell receptor (TCR) assembly, and TCR-mediated signaling. E2A and HEB acted in ETPs to establish and maintain a T-cell-lineage-specific enhancer repertoire, including regulatory elements associated with the Notch1, Rag1, and Rag2 loci. On the basis of these and previous observations, we propose that the E-Id protein axis specifies innate and adaptive lymphoid cell fate.
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•E2A and HEB act in concert to specify T cell fate•E protein activity in lymphoid progenitors suppresses aberrant ILC development•E2A and HEB establish a T-lineage-specific program of gene expression•The E-Id protein axis specifies the adaptive and innate lymphoid cell fate
Previous studies established that E proteins act at multiple stages to promote T-cell-lineage development. Miyazaki et al. demonstrate that E proteins establish T cell identity and suppress the development of thymic ILCs by modulating enhancer repertoires of genes associated with Notch signaling and TCRβ locus assembly.
A 10-year-old boy diagnosed with unresectable giant cell tumor of bone in the sacrum was treated with a bone modifying agent denosumab. Administration of denosumab showed excellent clinical response ...without any major complications, and the tumor was surgically removed afterwards. However, 4 months after discontinuing denosumab, the patient developed severe hypercalcemia (15.2 mg/dl). There was a sharp surge in the levels of bone resorption markers, indicating that disregulated overt bone resorption after the discontinuation of denosumab led to hypercalcemia. The patient was treated with bisphosphonate and barely recovered from the life-threatening conditions. This case shows that a robust rebound of bone resorption may occur following cessation of denosumab and suggests that hypercalcemia is an underappreciated side effect of denosumab therapy in children.
Tertiary lymphoid tissues (TLTs) facilitate local T and B cell interactions in chronically inflamed organs. However, the cells and molecular pathways that govern TLT formation are poorly defined. ...Here, we identified TNF superfamily CD153/CD30 signaling between 2 unique age-dependent lymphocyte subpopulations, CD153+PD-1+CD4+ senescence-associated T (SAT) cells and CD30+T-bet+ age-associated B cells (ABCs), as a driver for TLT expansion. SAT cells, which produced ABC-inducing factors IL-21 and IFN-γ, and ABCs progressively accumulated within TLTs in aged kidneys after injury. Notably, in kidney injury models, CD153 or CD30 deficiency impaired functional SAT cell induction, which resulted in reduced ABC numbers and attenuated TLT formation with improved inflammation, fibrosis, and renal function. Attenuated TLT formation after transplantation of CD153-deficient bone marrow further supported the importance of CD153 in immune cells. Clonal analysis revealed that SAT cells and ABCs in the kidneys arose from both local differentiation and recruitment from the spleen. In the synovium of aged rheumatoid arthritis patients, T peripheral helper/T follicular helper cells and ABCs also expressed CD153 and CD30, respectively. Together, our data reveal a previously unappreciated function of CD153/CD30 signaling in TLT formation and propose targeting the CD153/CD30 signaling pathway as a therapeutic target for slowing kidney disease progression.
Polycomb group (PcG) proteins are essential regulators of stem cells. PcG and trithorax group proteins mark developmental regulator gene promoters with bivalent domains consisting of overlapping ...repressive and activating histone modifications to keep them poised for activation in embryonic stem cells. Bmi1, a component of PcG complexes, maintains the self-renewal capacity of adult stem cells, but its role in multipotency remains obscure. Here we show that Bmi1 is critical for multipotency of hematopoietic stem cells (HSCs) and multipotent progenitors (MPPs). B cell lineage developmental regulator genes, Ebf1 and Pax5, appeared to be transcriptionally repressed by bivalent domains before lineage commitment. Loss of Bmi1 resulted in a resolution of bivalent domains at the Ebf1 and Pax5 loci, leading to their premature expression in HSC/MPPs accompanied by accelerated lymphoid specification and a marked reduction in HSC/MPPs. Thus, Bmi1 is required to reinforce bivalent domains at key developmental regulator gene loci to maintain lineage specification poised for activation in adult stem cells.
► Loss of Bmi1 causes premature activation of lineage-specific genes in HSCs ► Bmi1 reinforces bivalent chromatin domains at key developmental regulator gene loci ► Loss of Bmi1 enhances B cell lineage differentiation at the expense of T cell lineage ► Bmi1 inhibits HSC lineage specification to maintain the multipotent state
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