BackgroundThe orchestration of T cell responses, particularly CD8+ T cells, through complex epigenetic and transcriptional mechanisms, plays a crucial role in boosting anti-tumor immunity.1–3 The ...interplay between TET enzymes as essential epigenetic modulators and BATF, a central transcription factor for T cell functionality, stands out as a key regulatory mechanism.4 5 MethodsThis study draws upon our previous findings, where we identified the effects of TET deficiency on BATF expression, and its pivotal role in countering T cell exhaustion through the inhibition of TOX and NR4A. Additionally, we found that TOX and NR4a repressed IL-21 secretion in CAR-T cells. Based on these insights, we developed a novel approach by pairing TET knockout (KO) with IL-21-mediated BATF upregulation, integrating an IL-21 on/off switch using a destabilization domain, thus enabling controlled IL-21 secretion via a small molecule. The resulting impact on tumor-infiltrating CD8+ T cell survival, expansion, effector functionality, and exhaustion was systematically assessed.ResultsOur dual intervention significantly amplified the anti-tumor responses of CD8+ T cells. The data showcased a marked enhancement in the survival, expansion, and effector functionality of these cells within tumors, accompanied by a substantial reduction in exhaustion. These changes were reflected in the decreased expression of inhibitory receptors and exhaustion-linked transcription factors. Notably, our on/off switch system successfully controlled IL-21 secretion using a small molecule.ConclusionsThis research pioneers a promising therapeutic strategy that melds both epigenetic and transcriptional manipulation, specifically through TET inhibition and IL-21-driven BATF overexpression, enhanced by TOX and NR4a downregulation. The integrated approach, including the innovative on/off switch for IL-21 secretion, has the potential to significantly amplify CD8+ T cell anti-tumor responses. This multifaceted strategy opens new paths for refining and augmenting the effectiveness of cancer immunotherapy.AcknowledgementsThis work was supported by the New Faculty Startup Fund and Creative-Pioneering Researchers Program from Seoul National University, and the National Research Foundation of Korea (NRF) grant funded by the Korea government (MSIT)(No. RS-2023-00242443, RS-2023-00210035).ReferencesSeo H, González-Avalos E, Zhang W, et al. BATF and IRF4 cooperate to counter exhaustion in tumor-infiltrating CAR T cells. Nat Immunol 2021;22:983–995.Seo H, Chen J, Gonzalez-Avalos E, Samaniego-Castruita D, Das A. Wang YH, Lopez-Moyado IF, Georges RO, Zhang W, Onodera A, Wu C-J, Lu L-F, Hogan PG, Bhandoola A, Rao A. TOX and TOX2 transcription factors cooperate with NR4A transcription factors to impose CD8+ T cell exhaustion. Proc Natl Acad Sci USA. Jun 18 2019;116(25):12410–12415.Chen J, Lopez-Moyado IF, Seo H, Lio C-WJ, Hempleman LJ, Sekiya T, Yoshimura A, Scott-Browne JP, Rao A. NR4A transcription factors limit CAR T cell function in solid tumours. Nature. 2019;567:530–534.Jain N, Zhao Z, Feucht J, et al. TET2 guards against unchecked BATF3-induced CAR T cell expansion. Nature 2023;615:315–322.Fraietta JA, Nobles CL, Sammons MA, et al. Disruption of TET2 promotes the therapeutic efficacy of CD19-targeted T cells. Nature 2018;558:307–312.
The recent advent of DNA sequencing technologies facilitates the use of genome sequencing data that provide means for more informative and precise classification and identification of members of the ...Bacteria and Archaea. Because the current species definition is based on the comparison of genome sequences between type and other strains in a given species, building a genome database with correct taxonomic information is of paramount need to enhance our efforts in exploring prokaryotic diversity and discovering novel species as well as for routine identifications. Here we introduce an integrated database, called EzBioCloud, that holds the taxonomic hierarchy of the Bacteria and Archaea, which is represented by quality-controlled 16S rRNA gene and genome sequences. Whole-genome assemblies in the NCBI Assembly Database were screened for low quality and subjected to a composite identification bioinformatics pipeline that employs gene-based searches followed by the calculation of average nucleotide identity. As a result, the database is made of 61 700 species/phylotypes, including 13 132 with validly published names, and 62 362 whole-genome assemblies that were identified taxonomically at the genus, species and subspecies levels. Genomic properties, such as genome size and DNA G+C content, and the occurrence in human microbiome data were calculated for each genus or higher taxa. This united database of taxonomy, 16S rRNA gene and genome sequences, with accompanying bioinformatics tools, should accelerate genome-based classification and identification of members of the Bacteria and Archaea. The database and related search tools are available at www.ezbiocloud.net/.
The transcription factors nuclear factor of activated T cells (NFAT) and activator protein 1 (AP-1; Fos-Jun) cooperate to promote the effector functions of T cells, but NFAT in the absence of AP-1 ...imposes a negative feedback program of T cell hyporesponsiveness (exhaustion). Here, we show that basic leucine zipper ATF-like transcription factor (BATF) and interferon regulatory factor 4 (IRF4) cooperate to counter T cell exhaustion in mouse tumor models. Overexpression of BATF in CD8
T cells expressing a chimeric antigen receptor (CAR) promoted the survival and expansion of tumor-infiltrating CAR T cells, increased the production of effector cytokines, decreased the expression of inhibitory receptors and the exhaustion-associated transcription factor TOX and supported the generation of long-lived memory T cells that controlled tumor recurrence. These responses were dependent on BATF-IRF interaction, since cells expressing a BATF variant unable to interact with IRF4 did not survive in tumors and did not effectively delay tumor growth. BATF may improve the antitumor responses of CAR T cells by skewing their phenotypes and transcriptional profiles away from exhaustion and towards increased effector function.
Cancer immunotherapy has emerged as an effective therapeutic strategy to treat cancer. Among diverse immune populations, invariant natural killer T (iNKT) cells have shown potent antitumor activity ...by linking innate and adaptive immune systems. Upon activation by lipid antigens on CD1d molecules, iNKT cells rapidly produce various cytokines and trigger antitumor immunity directly or indirectly by activating other antitumor immune cells. Administration of a representative iNKT cell ligand alpha-galactosylceramide (α-GalCer) or α-GalCer-pulsed APCs effectively stimulates iNKT cells and thereby induces antitumor effects. In this review, we will introduce the biology and importance of NKT cells in antitumor immunity. Previous studies have demonstrated that iNKT cells not only activate various immune cells but also reinvigorate exhausted immune cells in the tumor microenvironment. Furthermore, we will summarize the major clinical trials utilizing iNKT-based immunotherapies.
During cancer immunoediting, loss of major histocompatibility complex class I (MHC-I) in neoplasm contributes to the evasion of tumours from host immune system. Recent studies have demonstrated that ...most natural killer (NK) cells that are found in advanced cancers are defective, releasing the malignant MHC-I-deficient tumours from NK-cell-dependent immune control. Here, we show that a natural killer T (NKT)-cell-ligand-loaded tumour-antigen expressing antigen-presenting cell (APC)-based vaccine effectively eradicates these advanced tumours. During this process, we find that the co-expression of Tim-3 and PD-1 marks functionally exhausted NK cells in advanced tumours and that MHC-I downregulation in tumours is closely associated with the induction of NK-cell exhaustion in both tumour-bearing mice and cancer patients. Furthermore, the recovery of NK-cell function by IL-21 is critical for the anti-tumour effects of the vaccine against advanced tumours. These results reveal the process involved in the induction of NK-cell dysfunction in advanced cancers and provide a guidance for the development of strategies for cancer immunotherapy.
Uncontrolled macrophage functions cause failure to resolve gut inflammation and has been implicated in the pathogenesis of inflammatory bowel disease (IBD). 15-Deoxy-Δ
12,14
-prostaglandin J
2
...(15d-PGJ
2
), one of endogenous lipid mediators formed from arachidonic acid during the inflammatory process, has been reported to terminate inflammation. However, the pro-resolving effect of 15d-PGJ
2
on intestinal inflammation and underlying molecular mechanisms remain largely unknown. In the present study, we examined the effects of 15d-PGJ
2
on the resolution of dextran sulfate sodium (DSS)-induced murine colitis that mimics human IBD. Pharmacologic inhibition of prostaglandin D synthase (PGDS) responsible for the synthesis of 15d-PGJ
2
hampered resolution of inflammation in the colonic mucosa of mice treated with DSS. Notably, intraperitoneal injection of 15d-PGJ
2
accelerated the resolution of experimentally induced colitis. 15d-PGJ
2
treatment reduced the number of neutrophils and M1 macrophages, while it increased the proportion of M2 macrophages. Moreover, 15d-PGJ
2
treated mice exhibited the significantly reduced proportion of macrophages expressing the pro-inflammatory cytokine, IL-6 with concomitant suppression of STAT3 phosphorylation in the colonic mucosa of mice administered 2.5% DSS in drinking water. Taken together, these findings clearly indicate that 15d-PGJ
2
, endogenously generated from arachidonic acid by cyclooxygenase-2 and PGDS activities in inflamed tissue, promotes resolution of intestinal colitis.
PSGL-1 (P-selectin glycoprotein-1) is a T cell-intrinsic checkpoint regulator of exhaustion with an unknown mechanism of action. Here, we show that PSGL-1 acts upstream of PD-1 and requires ...co-ligation with the T cell receptor (TCR) to attenuate activation of mouse and human CD8+ T cells and drive terminal T cell exhaustion. PSGL-1 directly restrains TCR signaling via Zap70 and maintains expression of the Zap70 inhibitor Sts-1. PSGL-1 deficiency empowers CD8+ T cells to respond to low-affinity TCR ligands and inhibit growth of PD-1-blockade-resistant melanoma by enabling tumor-infiltrating T cells to sustain an elevated metabolic gene signature supportive of increased glycolysis and glucose uptake to promote effector function. This outcome is coupled to an increased abundance of CD8+ T cell stem cell-like progenitors that maintain effector functions. Additionally, pharmacologic blockade of PSGL-1 curtails T cell exhaustion, indicating that PSGL-1 represents an immunotherapeutic target for PD-1-blockade-resistant tumors.
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•PSGL-1 restrains TCR signaling and glycolytic potential of CD8+ T cells•PSGL-1 deficiency limits CD8+ T cell exhaustion and supports precursor populations•Co-ligation of PSGL-1 and the TCR promotes T cell exhaustion in CD8+ T cells•PSGL-1 therapeutic blockade promotes T cell responses and melanoma tumor control
In this study, Hope et al. reveal intrinsic mechanisms through which the cell surface molecule PSGL-1 (P-selectin glycoprotein-1) modulates T cell responses and drives differentiation to terminal exhaustion in chronic virus infection and melanoma. Their study highlights the targetability of PSGL-1 as an emerging immune checkpoint blockade strategy.
Monocyte-derived dendritic cells (moDCs) have been shown to robustly expand during infection; however, their roles in anti-infectious immunity remain unclear. Here, we found that moDCs were ...dramatically increased in the secondary lymphoid organs during acute LCMV infection in an interferon-γ (IFN-γ)-dependent manner. We also found that priming by moDCs enhanced the differentiation of memory CD8
T cells compared to differentiation primed by conventional dendritic cells (cDCs) through upregulation of Eomesodermin (Eomes) and T cell factor-1 (TCF-1) expression in CD8
T cells. Consequently, impaired memory formation of CD8
T cells in mice that had reduced numbers of moDCs led to defective clearance of pathogens upon rechallenge. Mechanistically, attenuated interleukin-2 (IL-2) signaling in CD8
T cells primed by moDCs was responsible for the enhanced memory programming of CD8
T cells. Therefore, our findings unveil a specialization of the antigen-presenting cell subsets in the fate determination of CD8
T cells during infection and pave the way for the development of a novel therapeutic intervention on infection.
Objective
Lung sonography can be helpful to determine the position of a left-sided double-lumen tube (DLT). However, clinical experience is required for correct assessment. We investigated whether ...lung sonography can improve the diagnostic efficacy of determining the DLT position in novices and experts.
Methods
In this randomised prospective clinical study, 88 patients were allocated to two groups using auscultation or lung sonography for initial assessment of the DLT position. In each group, two repeated assessments were performed; the first was performed by a novice, and the second was performed by an expert. The final DLT position was confirmed by fibre-optic bronchoscopy. The primary outcome was the diagnostic efficacy (including overall accuracy, sensitivity, and specificity) in confirming the DLT position.
Results
In both the novices and experts, the specificity of determining the DLT position was significantly higher with lung sonography than auscultation (60.0% vs. 21.7% and 66.7% vs. 37.5%, respectively). Additionally, the predictability of an incorrect position was similar between the novices and experts using lung sonography (area under the curve of 0.665 and 0.690, respectively).
Conclusions
Lung sonography can improve the diagnostic efficacy of detecting an incorrect DLT position in both novices and experts.
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