Journal Club

We introduce interesting papers we selected for our journal club.

JC-059（Oct 31, 2024)
The type 2 cytokine Fc–IL-4 revitalizes exhausted CD8+ T cells against cancer

Nature. 2024 Oct;634(8034):712-720. doi: 10.1038/s41586-024-07962-4. Epub 2024 Sep 25.

Current cancer immunotherapy focuses on eliciting type 1 immune responses: terminal exhausted CD8+T cell possess strong cytotoxicity but survival deficiency. How can you maintain this population within TME & their effector function?

This study described the effect of IL-4 on CD8 T cells and an underlying mechanism. While type 1 & 2 responses are usually independent, this finding suggests IL-4 could orchestrate both, offering new insights for cancer immunotherapy.

by Ryoichi Maenosono @r_maenosono

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JC-058（Oct 29, 2024)
A prospective study of neoadjuvant pembrolizumab plus chemotherapy for resectable esophageal squamous cell carcinoma: The Keystone-001 trial

Cancer Cell. 2024 Oct 14;42(10):1747-1763.e7. doi: 10.1016/j.ccell.2024.09.008.

An increase in the TRGC2+ NKT cell fraction in the PB has been reported as a biomarker for predicting therapeutic response to pembrolizumab combined with cytotoxic chemotherapy in esophageal squamous cell carcinoma.  

Activity of the naive TRGC2+ NKT and the effector TRGC2+ NKT cell fraction, as well as enhanced expression of the CREM transcription factor in TRGC2+ NKT cells were observed in the group with a favorable response to treatment.

by Takuya Izumi @Takuya__Izumi

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JC-057（Oct 21, 2024)
Neoself-antigens are the primary target for autoreactive T cells in human lupus

Cell. 2024 Oct 17;187(21):6071-6087.e20. doi: 10.1016/j.cell.2024.08.025. Epub 2024 Sep 13.

Mori et al. demonstrated that unfolded proteins in ER are loaded on MHC-II to serve as “neoself-antigen”, inducing helper T-cell expansion and autoantibody production.

The invariant chain (Ii) binds to MHC-II in ER to prevent loading of unfolded proteins. However, when Ii expression is suppressed, unfolded self-proteins are load to MHC-II, serving as neoself-antigens.

by Masahiko Ajiro @Masahiko_Ajiro

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JC-056（Oct 17, 2024)
Distinct clinical outcomes and biological features of specific KRAS mutants in human pancreatic cancer

Cancer Cell. Volume 42, Issue 9, 9 September 2024, Pages 1614-1629.e5.

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JC-055（Oct 2, 2024)
Two-factor authentication underpins the precision of the piRNA pathway

Nature. 2024 Sep 18. doi: 10.1038/s41586-024-07963-3. Online ahead of print.

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JC-054（Sep 26, 2024)
Integrative analysis of neuroblastoma by single-cell RNA sequencing identifies the NECTIN2-TIGIT axis as a target for immunotherapy

Cancer Cell. 2024 Feb 12;42(2):283-300.e8. doi: 10.1016/j.ccell.2023.12.008. Epub 2024 Jan 4.

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JC-053（Sep 26, 2024)
RNA shielding of P65 is required to potentiate oncogenic inflammation in TET2 mutated clonal hematopoiesis

Cancer Discov. 2024 Aug 27. doi: 10.1158/2159-8290.CD-24-0093. Online ahead of print.

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JC-052（Sep 17, 2024)
Targeting the mSWI/SNF complex in POU2F-POU2AF transcription factor-driven malignancies

Cancer Cell. 2024 Aug 12;42(8):1336-1351.e9. doi: 10.1016/j.ccell.2024.06.006. Epub 2024 Jul 18.

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JC-051（Sep 13, 2024)
A non-canonical role for a small nucleolar RNA in ribosome biogenesis and senescence

Cell. 2024 Aug 22;187(17):4770-4789.e23. doi: 10.1016/j.cell.2024.06.019. Epub 2024 Jul 8.

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JC-050（Sep 6, 2024)
Genome-wide repeat landscapes in cancer and cell-free DNA

Sci Transl Med. 2024 Mar 13;16(738):eadj9283. doi: 10.1126/scitranslmed.adj9283. Epub 2024 Mar 13.

Repeat sequences, comprising over 50% of the genome, are challenging to align. Annapragada et al. identified 1.2 billion unique 24-bp kmers within these repeats and developed the ARTEMIS algorithm to address this limitation.

ARTEMIS delineated cancer-specific repeat landscapes, enabling to identify tissue of origin of cancer based on cfDNA. This innovative approach has significant implications for tumorigenesis research, early detection, and disease monitoring.

by Asuka Kawachi @AsukaKawachi

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JC-049（Sep 4, 2024)
Nynrin preserves hematopoietic stem cell function by inhibiting the mitochondrial permeability transition pore opening

Cell Stem Cell. 2024 Jun 25:S1934-5909(24)00215-7. doi: 10.1016/j.stem.2024.06.007.

Nynrin is highly expressed in LT-HSCs and plays a critical role in maintaining HSC. By inhibiting mPTP opening via Ppif, Nynrin enhances HSC self-renewal and resistance to radiation, offering potential therapeutic targets.

Nynrin deficiency leads to reduced HSC function, increased oxidative stress, and higher mortality rates post-radiation. These results suggest new avenues for protecting stem cells during cancer therapies such as radiation treatment.

by Hirofumi Yamauchi @HiroYama0123

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JC-048（Aug 16, 2024)
Selective advantage of mutant stem cells in human clonal hematopoiesis is associated with attenuated response to inflammation and aging

Cell Stem Cell. 2024 Aug 1;31(8):1127-1144.e17. doi: 10.1016/j.stem.2024.05.010. Epub 2024 Jun 24.

A single-cell multi-omics, which combines high-fidelity genotyping with transcriptional profiling, enabled to separately analyze mutant and non-mut hematopoietic stem and progenitor cells (HSPCs) in clonal hematopoiesis (CH).

HSPCs from CH samples exhibited elevated inflammation and aging gene expression, while mutated HSPCs showed a reduced inflammatory response compared to wild-type, suggesting a functional advantage due to differential inflammation impact.

by Tomoya Muto @mucyotomo

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JC-047（Aug 13, 2024)
Mutant IDH1 inhibition induces dsDNA sensing to activate tumor immunity

Science. 2024 Jul 12;385(6705):eadl6173. doi: 10.1126/science.adl6173. Epub 2024 Jul 12.

Inhibition of mutant IDH1 activates antitumor immunity by inducing a "viral mimicry" state through the activation of transposon expression, which triggers cGAS/STING/IRF3 activation.

by Minori Koizumi

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JC-046（Aug 5, 2024)
Germline-mediated immunoediting sculpts breast cancer subtypes and metastatic proclivity

Science. 2024 May 31;384(6699):eadh8697. doi: 10.1126/science.adh8697. Epub 2024 May 31.

Contrary to previous thoughts, germline benign mutation epitopes (GEB) are subject to immunosurveillance. Study shows people with HLA alleles capable of presenting HER2 GP2/E75 are less prone to HER2+ breast cancer.

High GEB invasive cancers that have surpassed the selection are linked with poor prognosis. GEB ties cancer phenotypes to a new concept of subtype determination, anticipating GEB measurement could aid in predicting subtypes, risk classification, etc.

by Rei Kudo @Reik0110

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JC-045（Jul 30, 2024)
Transient loss of Polycomb components induces an epigenetic cancer fate

Nature. 2024 May;629(8012):688-696. doi: 10.1038/s41586-024-07328-w. Epub 2024 Apr 24.

Tumors have been considered to arise only from permanent genetic mutations, however, Parreno et al. demonstrated that transient epigenetic disruption is sufficient to support tumor initiation and progression in flies.

Transient Knockdown of polycomb protein leads to irreversible transcription activation of genes, especially related to JAK-STAT signaling (Stat92E, Zfh1 etc), which binds and irreversibly dysregulates gene transcription related to tumor formation.

by Mina Yoshida

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JC-044（Jul 26, 2024)
Clonal hematopoiesis driven by mutated DNMT3A promotes inflammatory bone loss

Cell. 2024 Jul 11;187(14):3690-3711.e19. doi: 10.1016/j.cell.2024.05.003. Epub 2024 Jun 4.

A study demonstrated that DNMT3A-asosciated #CHIP increases the risk of severe periodontitis, potentially driven by the activation of DNMT3A mut osteoclast lineage and functional decline of Tregs.

by Hirofumi Yamauchi @HiroYama0123

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JC-043（Jul 23, 2024)
GPATCH8 modulates mutant SF3B1 mis-splicing and pathogenicity in hematologic malignancies

Mol Cell. 2024 May 16;84(10):1886-1903.e10. doi: 10.1016/j.molcel.2024.04.006. Epub 2024 Apr 29.

In SF3B1 mutant tumor cells, GPATCH8 induces missplicing by competing with SUGP1 to bind with DHX15, leading to aberrant branchpoint recognition.

The deletion of GPATCH8 promotes the binding of DHX15 to SUGP1, which in turn corrects the mis-splicing. Pharmacologic approaches to disable GPATCH8 potentially improve SF3B1 mutation-dependent mis-splicing abnormalities in various cancers.

by Takuya Izumi @Takuya__Izumi

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JC-042（Jul 12, 2024)
Selective haematological cancer eradication with preserved haematopoiesis

Nature. 2024 Jun;630(8017):728-735. doi: 10.1038/s41586-024-07456-3. Epub 2024 May 22.

A paper proposing a new transplantation strategy for hematologic malignancies by combining an anti-CD45 #ADC with hematopoietic stem cells (HSC) shielded by a single amino acid substitution in CD45.

by Minori Koizumi

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JC-041（Jul 1, 2024)
MYCT1 controls environmental sensing in human haematopoietic stem cells

Nature. 2024 Jun;630(8016):412-420. doi: 10.1038/s41586-024-07478-x. Epub 2024 Jun 5.

A study shows that MYCT1 helps maintain the stemness and function of hematopoietic stem cells (HSCs), improving transplant success rates.

MYCT1 influences signal transduction pathways via endocytosis regulation, linking endocytosis and HSC control in an intriguing way.

by Michiko Kurikawa

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JC-040（Jun 25, 2024)
Time-resolved profiling of RNA binding proteins throughout the mRNA life cycle

Mol Cell. 2024 May 2;84(9):1764-1782.e10. doi: 10.1016/j.molcel.2024.03.012. Epub 2024 Apr 8.

Choi et al. labeled RNA transcribed within cells and collected the RBPs that bind to the RNA at multiple time points for mass analysis, demonstrating which stages of the RNA lifecycle more than 800 RBPs are involved in.

This data can be accessed at http://chronology.rna.snu.ac.kr.

Based on the discrepancies between the binding time points and known functions, new functions for some RBPs were also inferred.

by Mina Yoshida

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JC-039（Jun 14, 2024)
hnRNPM protects against the dsRNA-mediated interferon response by repressing LINE-associated cryptic splicing

Mol Cell. 2024 Jun 6;84(11):2087-2103.e8. doi: 10.1016/j.molcel.2024.05.004. Epub 2024 May 29.

New research shows the RNA-binding protein hnRNPM binds to pseudo splice sites in #LINEs within deep introns. This binding suppresses cryptic splicing and reduces type I interferon response from dsRNA.

Loss of hnRNPM leads to cryptic exons with #LINE1 or #Alu element and produces dsRNAs, which activates type I interferon and immune cells. This suggests that targeting hnRNPM might contribute a novel cancer #immunotherapy.

by Ryoichi Maenosono @r_maenosono

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JC-038（Jun 5, 2024)
FLT3L governs the development of partially overlapping hematopoietic lineages in humans and mice

Cell. 2024 May 23;187(11):2817-2837.e31. doi: 10.1016/j.cell.2024.04.009. Epub 2024 May 3.

A study analyzing a family with germline FLT3LG mutations leading to BM failure and susceptibility to infections, showing that FLT3L has different roles in hematopoiesis between humans and mice as follows:

FLT3L deficiency affects:
Mice → DC, B, NK cells
Humans → DC, B, Mono

by Takuya Izumi

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JC-037（Jun 3, 2024)
Genome organization around nuclear speckles drives mRNA splicing efficiency

Nature. 2024 May;629(8014):1165-1173. doi: 10.1038/s41586-024-07429-6. Epub 2024 May 8.

Bhat @_prashantbhat et al. demonstrated that genes localized near nuclear speckles display higher spliceosome concentrations, indicating that proximity to nuclear speckles is a major determinant for RNA splicing efficiency.

Nuclear speckles are membraneless organelle, where various splicing factors locate. The current study provides direct evidence for the role of nuclear speckles in splicing regulation, answering a long-lasting question of its functional significance.

by Masahiko Ajiro @Masahiko_Ajiro

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JC-036（May 30, 2024)
Alternative polyadenylation determines the functional landscape of inverted Alu repeats

Mol Cell. 2024 Mar 21;84(6):1062-1077.e9. doi: 10.1016/j.molcel.2024.01.008. Epub 2024 Feb 2.

Inverted Alu repeats (IRAlus) form a double-stranded hairpin structure in RNA. Ku et al. used J2 antibody to capture these structures and identified approximately 650 endogenous mRNAs with novel IRAlus.

dsRNA formed by 3'UTR IRAlus is sequestered in nuclear speckles, reducing translation efficiency. When IRAlus in MDM2are lost due to 3'UTR shortening, its expression increases and #p53 expression decreases.

Inhibiting CSTF2 binding, which performs this cleavage, with #ASO (antisense oligonucleotide) restored p53 function, indicating potential therapeutic applications.

by Michiko Kurikawa

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JC-035（May 27, 2024)
RNA aggregates harness the danger response for potent cancer immunotherapy

Cell. 2024 May 9;187(10):2521-2535.e21. doi: 10.1016/j.cell.2024.04.003. Epub 2024 May 1.

The authors developed a mRNA deliverying system, self-assembling multi-lamellar lipid particle aggregates (RNA-LPAs), which enhanced innate immune activation through the RIG1-MAVS pathway and enabled to improve the TME.They conducted a First in human trial of pp65 mRNA-LPAs for glioma patients and observed Type I IFN induction and subsequent activation of antitumor immunity in the glioma tumor microenvironment.

by Asuka Kawachi @AsukaKawachi

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JC-034（May 14, 2024)
Universal recording of immune cell interactions in vivo

Nature. 2024 Mar;627(8003):399-406. doi: 10.1038/s41586-024-07134-4. Epub 2024 Mar 6.

While spatial analysis insufficiently delineates physical interaction between immune cells, a novel method that records cell-cell interaction via transferring a peptide substrate onto acceptor side, has been developed as uLIPSTIC.
Because this technique can record a wide range of cellular interaction, it can reveal correlations between cell-cell contact and gene signatures universally, suggesting that uLIPSTIC could generate unexpected hypotheses.

by Ryoichi Maenosono @r_maenosono

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JC-033（May 9, 2024)
Cancer SLC6A6-mediated taurine uptake transactivates immune checkpoint genes and induces exhaustion in CD8+ T cells

Cell. 2024 Apr 25;187(9):2288-2304.e27. doi: 10.1016/j.cell.2024.03.011. Epub 2024 Apr 1.

The taurine transporter SLC6A6 is highly expressed in tumor cells, increases taurine uptake and promotes tumor progression. Taurine consumption by tumor cells causes a deficiency in CD8 T cells, inducing endoplasmic reticulum stress.
As a result, the PERK-JAK1-STAT3 pathway induces ATF4, promoting immune checkpoint gene transcription and T cell exhaustion. The clinical trial of taurine supplementation + chemo + immune checkpoint inhibitors already began; outcomes awaited.

by Tomoya Muto @mucyotomo

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JC-032（May 2, 2024)
Sexual dimorphism in skin immunity is mediated by an androgen-ILC2-dendritic cell axis

Science. 2024 Apr 12;384(6692):eadk6200. doi: 10.1126/science.adk6200. Epub 2024 Apr 12.

While sexual dimorphisms in immune function are widely observed, underlying mechanisms have been poorly understood. Here, androgen-dependent suppression of type 2 innate lymphoid cells (ILC2s) was shown as a master player.

Through single-cell RNA-seq of mouse skin, ILC2s were identified as lymphoid cells with the highest androgen receptor and found inactivated by androgen. This study suggests potential benefit of hormone control for immune therapy.

by Masahiko Ajiro @Masahiko_Ajiro

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JC-031（Apr 30, 2024)
Long-lasting mRNA-encoded interleukin-2 restores CD8+ T cell neoantigen immunity in MHC class I-deficient cancers

Cancer Cell. 2024 Apr 8;42(4):568-582.e11. doi: 10.1016/j.ccell.2024.02.013. Epub 2024 Mar 14.

MHC class I loss leads to a substantial immune desertification of the TME and the resistance to therapies. mRNA-encoded IL-2 restores immune cell infiltrated by IFNg+CD8+ T cells recognizing neoantigens cross-presented by macrophages.

This paper provided a new therapeutic strategy against MHC class I antigen presentation deficiency, which is a common cancer immune escape mechanism. First-in-human phase I trial is now ongoing. Combining IL-2 with #ICI could further enhance their therapeutic efficacy.

by Rei Kudo @Reik0110

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JC-029（Apr 5, 2024)
An iron rheostat controls hematopoietic stem cell fate

Cell Stem Cell. 2024 Mar 7;31(3):378-397.e12. doi: 10.1016/j.stem.2024.01.011. Epub 2024 Feb 22.

This study revealed the critical role of iron homeostasis in stem cell fate determination, underscoring the enhanced regenerative potential through the strategic limitation of iron availability.

Iron-dependent regulation in aged HSPCs, mediated by Tip60, holds promise for cell rejuvenation. Insights into the iron response, fatty acid metabolism, and Tip60 activation offer novel avenues to mitigate age-related stem cell dysfunction.

by Hirofumi Yamauchi @HiroYama0123

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JC-028（Mar 28, 2024)
Targeting PRMT9-mediated arginine methylation suppresses cancer stem cell maintenance and elicits cGAS-mediated anticancer immunity

Nat Cancer. 2024 Feb 27. doi: 10.1038/s43018-024-00736-x. Online ahead of print.

Inhibiting PRMT9 demonstrates anti-leukemic effects, disrupting arginine methylation on exoribonuclease XRN2 and poly(A) binding protein PABPC1, thus causing DNA damage and hindering translation.

PRMT9 inhibition also shows extracellular effects, triggering dendritic & T cell cross-priming via cGAMP release, activating anti-tumor immunity. Indeed, potent anti-tumor effects were demonstrated in combination with a #checkpoint inhibitor.

by Tomoya Muto @mucyotomo

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JC-027（Mar 25, 2024)
Neutrophil profiling illuminates anti-tumor antigen-presenting potency

Cell. 2024 Mar 14;187(6):1422-1439.e24. doi: 10.1016/j.cell.2024.02.005. Epub 2024 Mar 5.

Neutrophils in cancer show dual roles. Single-cell transcriptome analysis across 17 cancer types unveils 10 distinct states, highlighting their remarkable complexity.

Antigen-presenting HLA-DR+CD74+ neutrophils linked to favorable outcomes and increased by leucine, acetyl-CoA metabolism and H3K27ac modification of HLA-II genes. Leucine diet and delivery of antigen-presenting neutrophils enhanced anti-PD-1 therapy.

by Mina Yoshida

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JC-026（Mar 18, 2024)
Integrative analysis of neuroblastoma by single-cell RNA sequencing identifies the NECTIN2-TIGIT axis as a target for immunotherapy

Cancer Cell. 2024 Feb 12;42(2):283-300.e8. doi: 10.1016/j.ccell.2023.12.008. Epub 2024 Jan 4.

Single-cell RNA-sequencing of neuroblastoma including pre- and post-chemotherapy demonstrated that dysfunction of NK/T cells is associated with immunosuppressive interaction between NECTIN2 and TIGIT.

Anti-TIGIT enhances immune responses against tumors and improves survival in vivo.  Combining the blockade of immune checkpoints TIGIT and PD-L1 offers a promising therapeutic approach for chemotherapy-resistant neuroblastoma.

by Rei Kudo @Reik0110

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JC-025（Mar 8, 2024)
SMARCAL1 is a dual regulator of innate immune signaling and PD-L1 expression that promotes tumor immune evasion

Cell. 2024 Feb 15;187(4):861-881.e32. doi: 10.1016/j.cell.2024.01.008. Epub 2024 Jan 31.

Loss of SMARCAL1➡️a dual role in immune evasion.

✅increases genomic instability➡️activates innate immunity through cGAS-STING signaling pathway.
✅affects chromatin accessibility, suppressing PD-L1 expression.

by Michiko Kurikawa

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JC-024（Mar 1, 2024)
Inherited blood cancer predisposition through altered transcription elongation

Cell. 2024 Feb 1;187(3):642-658.e19. doi: 10.1016/j.cell.2023.12.016. Epub 2024 Jan 12.

UK Biobank data on 160k+ individuals revealed rare myeloid tumor variants via RVAS. Partial loss of CTR9 gene, part of PAF1 complex, significantly boosts stem cell self-renewal, elevating blood cancer risk tenfold. 

CTR9 intriguingly acts against the Super Elongation Complex recognition, essential for the transcription elongation of genes needed for HSC self-replication.

by Hirofumi Yamauchi @HiroYama0123

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JC-023（Feb 21, 2024）
A TCF4-dependent gene regulatory network confers resistance to immunotherapy in melanoma

Cell. 2024 Jan 4;187(1):166-183.e25. doi: 10.1016/j.cell.2023.11.037.

On exploring the mechanism of immune checkpoint blockade (ICB), melanoma ecosystem of early on-treatment sample demonstrated that mesenchymal-like (MES) state and its regulatory gene TCF4 may influence the TME and resistance to ICB.

Both single-cell RNA-seq and spatial omics analysis highlighted elevated TCF4 in early on-treatment samples, linking it to immune response suppression. This sheds light on TCF4's role in cancer progression, paving the way for targeted strategies.

by Ryoichi Maenosono @r_maenosono

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JC-022（Feb 15, 2024）
Hyperglycosylation of prosaposin in tumor dendritic cells drives immune escape

Science. 2024 Jan 12;383(6679):190-200. doi: 10.1126/science.adg1955. Epub 2024 Jan 11.

Prosaposin (pSAP) induces tumor immunity through CD8+ T cells; however, pSAP undergoes hyperglycosylation mediated by TGF-β in DCs. This diminishes antigen presentation capacity, resulting in immune evasion.

Recombinant pSAP with optimized glycosylation restores the immune response against tumors. When combined with anti-PD-L1, it effectively suppresses melanoma growth in mice, indicating a promising approach to overcoming resistance to #checkpointinhibitor.

by Tetsuro Takasaki

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JC-021（Feb 7, 2024）
Deciphering cell states and genealogies of human hematopoiesis

Nature. 2024 Jan 22. doi: 10.1038/s41586-024-07066-z. Online ahead of print.

The new single-cell lineage analysis pipline, ReDeeM, was reported by Sankaran @bloodgenes and Weissman @JswLab . With ~10-fold increase in resolution, new insights in lineage preference and age-associated clonality were revealed.

Mitochondrial DNA (mtDNA) is suitable as endogenous cell-lineage barcodes for its copy number (100-1,000/cell) and high mutation rates. ReDeeM leverages custom probes for condensing mtDNA sequence to enhance detection rate of mtDNA mutations.

by Masahiko Ajiro @Masahiko_Ajiro

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JC-020（Feb 1, 2024）
Tumour circular RNAs elicit anti-tumour immunity by encoding cryptic peptides

Nature. 2024 Jan;625(7995):593-602. doi: 10.1038/s41586-023-06834-7. Epub 2023 Dec 13.

Mass spectrometry of HLA-I immunopeptidome, coupled with Ribo-seq, revealed cryptic antigenic peptides translated from tumor-specific circRNA: circFAM53B. These peptides primed naïve CD4+&CD8+ T cells, inducing anti-tumor immunity.
Furthermore, circFAM53B expression correlated with cytotoxic T cell infiltration and improved survival in breast cancer and melanoma patients. Vaccination with tumor-specific circRNA or its peptides in tumor mice exhibited effective tumor control.
While CDS mutations with effective antigenicity are rare, cryptic peptides from circRNA could be potential targets for #immunotherapy.

by Mina Yoshida

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JC-019（Jan 24, 2024）
Super-enhancer RNA m6A promotes local chromatin accessibility and oncogene transcription in pancreatic ductal adenocarcinoma

Nat Genet. 2023 Dec;55(12):2224-2234. doi: 10.1038/s41588-023-01568-8. Epub 2023 Nov 13.

A new role of seRNA m6A modifications to controle chromatin structure were uncovered. CFL1 and Mettl3 collaborate to methylate seRNA --> TYHDC2 recognizes this, forming a complex with MLL1 and leading to H3K4 methylation.

High seRNA m6A levels in PDAC patients are associated with poor prognosis, and overexpression of CFL1 in cancer cells correlates with increased malignancy. This suggests that seRNA methylation via CFL1 may drive pancreatic cancer and could be a potential therapeutic target.

by @AsukaKawachi

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JC-018（Jan 22, 2024）
Breast cancer remotely imposes a myeloid bias on haematopoietic stem cells by reprogramming the bone marrow niche

Nat Cell Biol. 2023 Dec;25(12):1736-1745. doi: 10.1038/s41556-023-01291-w. Epub 2023 Nov 30.

The authors discovered that cancer-related #inflammation distantly alters transcription and spatial distribution of both HSCs and MSCs within the BM niche, sparking myeloid-biased differentiation.

The myeloid differentiation of HSCs is related to the osteogenic tendencies of MCSs. Further investigation of the molecular crosstalk between HSC and MSC, as well as the role of cancer cell-derived factors in driving differentiation are required.

by Michiko Kurikawa

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JC-017（Jan 10, 2024）
An IL-4 signalling axis in bone marrow drives pro-tumorigenic myelopoiesis

Nature. 2024 Jan;625(7993):166-174. doi: 10.1038/s41586-023-06797-9. Epub 2023 Dec 6.

In non-small cell lung cancer (#NSCLC), IL-4 derived from eosinophils and basophils in the bone marrow acts on granulocyte-monocyte progenitor cells, suppressing anti-tumor immune responses mediated by monocyte-derived macrophages.

A clinical trial showed that combining an IL-4 inhibitor with an immune checkpoint inhibitor was effective in treating NSCLC. This discovery could lead to the development of novel therapies for a broad spectrum of cancers.

by Tomoya Muto @mucyotomo

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JC-016（Dec 28, 2023）
ZNF683 marks a CD8+ T cell population associated with anti-tumor immunity following anti-PD-1 therapy for Richter syndrome

Cancer Cell. 2023 Oct 9;41(10):1803-1816.e8. doi: 10.1016/j.ccell.2023.08.013. Epub 2023 Sep 21.

Examining the mechanism of Richter syndrome, derived from CLL, responding to #ICI using scRNA-seq on serial BM samples. Responders displayed intermediate exhausted CD8 effector/memory T cells expressing the transcription factor ZNF683.

Using CUT&RUN analysis, the study revealed that ZNF683 binds to regulatory regions of immune-related genes such as CD69 and TCF7, regulating T cell pathways. Notably, ZNF683 expression was seen in PB and solid cancers, suggesting a potential key role for ZNF683 in #ICI therapy.

by Ryoichi Maenosono

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JC-015（Dec 25, 2023）
Epigenetic regulation during cancer transitions across 11 tumour types

Nature. 2023 Nov;623(7986):432-441. doi: 10.1038/s41586-023-06682-5. Epub 2023 Nov 1.

Unlocking the power of simultaneous epigenome and transcriptome profiling in clinical samples using snATAC-seq and snRNA-seq. Discovering cancer-specific and general drivers like TP53, hypoxia, and TNF signaling.

This study uncovered the epigenetic change underpinning the transition from normal to cancer by comparing single-nucleus in the closest normal cells and cancer cells in clinical samples. The dynamic epigenetic change might be a new therapeutic target.

by Rei Kudo @Reik0110

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JC-014（Dec 13, 2023）
Single-cell multi-omics defines the cell-type-specific impact of splicing aberrations in human hematopoietic clonal outgrowths

Cell Stem Cell. 2023 Sep 7;30(9):1262-1281.e8. doi: 10.1016/j.stem.2023.07.012. Epub 2023 Aug 14.

GoT-Splice, the new multi-omics pipeline integrating long-read transcriptome, has been established for single-cell analysis. It's application to MDS revealed enrichment of SF3B1 mutant cells in erythroid progenitor cells.

GoT-Splice can capture RNA splicing alterations with ONT long-read sequencing, providing an innovative method to dissect functional relationship between aberrant RNA splicing and cancer pathology.

by Masahiko Ajiro @Masahiko_Ajiro

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JC-013（Dec 8, 2023）
A T cell receptor targeting a recurrent driver mutation in FLT3 mediates elimination of primary human acute myeloid leukemia in vivo

Nat Cancer. 2023 Oct;4(10):1474-1490. doi: 10.1038/s43018-023-00642-8. Epub 2023 Oct 2.

The authors utilized a unique method by introducing a set of tumor-specific neoantigen candidates into dendritic cells via minigene, eliciting a response from naïve T cells. 
In AML PDX models, they achieved minimal residual disease negativity and successfully eliminating CD34+ AML cells, paving the way for the future development of T cell immunotherapy targeting FLT3 D835Y mutations. 

by Hirofumi Yamauchi @HiroYama0123 

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JC-012（Dec 4, 2023）
Single-cell CRISPR screens in vivo map T cell fate regulomes in cancer

Nature. 2023 Nov 15. doi: 10.1038/s41586-023-06733-x. Online ahead of print.

Combined in vivo CRISPR screening with scRNA-seq (scCRISPR screen) identified the gene network and checkpoints controlling the differentiation of CD8 positive T cells (CTLs).
IKAROS-TCF1 pathway promotes the differentiation of exhausted T cells (Tex), while the ETS-BATF acts suppressively. The RPBJ-IRF3 axis induces the ultimate exhaustion of Tex. Identifying new targets is anticipated to contribute to improving resistance to ICIs.

by @AsukaKawachi

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JC-011（Nov 27, 2023）
An Inflammatory Checkpoint Generated by IL1RN Splicing Offers Therapeutic Opportunity for KRAS-Mutant Intrahepatic Cholangiocarcinoma

Cancer Discov. 2023 Oct 5;13(10):2248-2269. doi: 10.1158/2159-8290.CD-23-0282.

Intrahepatic cholangiocarcinoma with #KRAS mutation created an anti-tumor microenvironment by upregulating the expression of interleukin 1 receptor antagonist (IL1RN)-201 and IL1RN-203 through alternative splicing.

Alterations in the TME due to alternative splicing of IL1RN underpin the synergistic effects of IL-1 and PD-1 inhibitors. It is intriguing that KRAS mutations, rather than splicing factors, trigger distinctive alternative splicing related to inflammation.

by Kazuki Nishimura

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JC-010（Nov 15, 2023）
Epigenetic balance ensures mechanistic control of MLL amplification and rearrangement

Cell. 2023 Oct 12;186(21):4528-4545.e18. doi: 10.1016/j.cell.2023.09.009. Epub 2023 Oct 2.

This study showed that an imbalance in H3K9me01月02日 and CTCF occupancy at #MLL contributes to its amplifications and rearrangements. G9a inhibition suppresses DOX-induced MLL alterations by reduction of KDM3B and CTCF proteins.

These findings may facilitate developing the novel therapies for cancer by controlling the emergence of treatment-induced MLL amplifications and rearrangements.

by Tomoya Muto @mucyotomo

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JC-009（Nov 9, 2023）
CD300ld on neutrophils is required for tumour-driven immune suppression

Nature. 2023 Sep;621(7980):830-839. doi: 10.1038/s41586-023-06511-9. Epub 2023 Sep 6.

CD300ld, identified through in vivo CRISPR screening targeting membrane proteins, suppresses immune responses by recruiting polymorphonuclear-MDSCs to tumors, key components of the TME. This contributes to tumor growth.

Furthermore, S1008A/9A acts downstream of CD300ld and is regulated by STAT3. Inactivating CD300ld leads to remodeling of the TME, suggesting a potential synergistic effect with anti-PD-1 antibodies. Exciting possibilities for future therapies!

by Tetsuro Takasaki

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JC-008（Nov 1, 2023）
PD-1 instructs a tumor-suppressive metabolic program that restricts glycolysis and restrains AP-1 activity in T cell lymphoma

Nat Cancer. 2023 Oct;4(10):1508-1525. doi: 10.1038/s43018-023-00635-7. Epub 2023 Sep 18.

PD-1 deficiency in T cell non-Hodgkin #lymphoma triggers AP-1 activation via glycolytic reprogramming and acetyl-CoA production, driving disease progression.

The study uncovers a novel role for PD1 as a vital energy metabolism gatekeeper. The AKT-mTOR-HIF1α-ACLY axis emerges as a potential therapeutic target for PDCD1-mutated T cell non-Hodgkin lymphoma.

by Rei Kudo @Reik0110

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JC-007（Oct 25, 2023）
Sites of transcription initiation drive mRNA isoform selection

Cell. 2023 May 25;186(11):2438-2455.e22. doi: 10.1016/j.cell.2023.04.012. Epub 2023 May 12.

The transcription start site (TSS) and polyadenylation site (PAS) are selected from multiple locations, producing diverse mRNA. #Long Read Sequencing identified the correspondence b/w global TSS and PAS selection in the nervous system.
Tissue-specific trends were observed in the usage of TSS, regulating tissue-specific #mRNA isoforms through the selection of corresponding PAS. Genes with TSS-PAS relationships were characterized by epigenetic modifications and recruitment of binding factors.

by Mina Yoshida

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JC-006（Oct 18, 2023）
NSUN2 is a glucose sensor suppressing cGAS/STING to maintain tumorigenesis and immunotherapy

Cell Metab. 2023 Oct 3;35(10):1782-1798.e8. doi: 10.1016/j.cmet.2023.07.009. Epub 2023 Aug 15.

Direct glucose binding to NSUN2 triggers its oligomerization and activation, ensuring continuous TREX2 expression. This mechanism plays a crucial role in oncogenesis and resistance to anti-PD-L1 therapy.  

by @HiroYama0123 

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JC-005（Oct 11, 2023）
CD44+ lung cancer stem cell-derived pericyte-like cells cause brain metastases through GPR124-enhanced trans-endothelial migration

Cancer Cell. 2023 Sep 11;41(9):1621-1636.e8. doi: 10.1016/j.ccell.2023.07.012. Epub 2023 Aug 17.

CD44+ #lungcancer stem cell-derived pericytes acquire migratory capability and induce brain #metastasis though a de-differentiation process, which is driven by GPR124-mediated Wnt-βcatenin activation. 

by Michiko Kurikawa

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JC-004（Oct 2, 2023）
The CD58-CD2 axis is co-regulated with PD-L1 via CMTM6 and shapes anti-tumor immunity

Cancer Cell. 2023 Jul 10;41(7):1207-1221.e12. doi: 10.1016/j.ccell.2023.05.014. Epub 2023 Jun 15.

Defects in the CD58-CD2 axis lead to #ImmuneEvasion by inactivating T cells and hindering their infiltration and proliferation. CRISPR screen identified CMTM6 as a key regulator of CD58.

by Kazuki Nishimura

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JC-003（Sep 20, 2023）
A distinct stimulatory cDC1 subpopulation amplifies CD8+ T cell responses in tumors for protective anti-cancer immunity

Cancer Cell 2023 Aug 14;41(8):1498-1515.e10. doi: 10.1016/j.ccell.2023.06.008. Epub 2023 Jul 13

Exciting #DeepLearning research unveils the intricate interactions between MHCIIhiCCR7neg cDC1 and CD8+ T cells, offering new possibilities for advancing cancer treatment strategies.  #CancerResearch #Immunology

by Ryoichi Maenosono

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JC-002（Sep 13, 2023）
Highly multiplexed bioactivity screening reveals human and microbiota metabolome-GPCRome interactions

Cell 2023 Jul 6;186(14):3095-3110.e19. doi: 10.1016/j.cell.2023.05.024. Epub 2023 Jun 14

A novel GPCR ligand screen system "PRESTO-Salsa" can screen >300 GPCRs in a well. Ligand binding to a GPC --> arrestin-TEV recruitment --> tTA cleavage --> tTA activates the barcode transcription --> the activated GPCR will be identified by NGS.

Conducting a thorough ligand screen for GPCRs, the largest membrane receptor protein family, can be quite challenging. "PRESTO-Salsa" will streamline GPCR ligand screening, advancing our grasp of their physiological roles.  #GPCR #Research

by Tetsuro Takasaki

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JC-001（Sep 6, 2023）
RBFOX2 modulates a metastatic signature of alternative splicing in pancreatic cancer

Nature 2023 May;617(7959):147-153. doi: 10.1038/s41586-023-05820-3. Epub 2023 Mar 22

Rotem lab identified loss of splicing factor RBFOX2 as a functional determinant of PDA (pancreatic ductal adenocarcinoma) metastatic progression. Splicing and motif analysis identified that RBFOX2 motifs were enriched in primary vs metastatic samples. Target genes of RBFOX2 including MPRIP regulate the RHO GTPase pathway and metastatic potential of PDA. These observations highlight further potential of splicing alterations in cancer research.

by Masahiko Ajiro

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