
HER2陽性乳がんでは免疫抑制的な腫瘍関連マクロファージ(M2型)が優位であるが、アルギニン代謝の調節によりM1型マクロファージへの再プログラミングが可能となり、抗腫瘍免疫応答を誘導できる。


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HER2+ breast tumors have abundant immune-suppressive cells, including M2-type tumor associated macrophages (TAMs). While TAMs consist of the immune-stimulatory M1-type and immune-suppressive M2-type, M1/M2-TAM ratio is reduced in immune-suppressive tumors, contributing to their immunotherapy refractoriness. M1 vs. M2-TAM formation depends on differential arginine metabolism, where M1-TAMs convert arginine to nitric oxide (NO) and M2- TAMs convert arginine to polyamines (PAs). We hypothesize that such distinct arginine metabolism in M1- vs M2-TAMs is attributed to different availability of BH4 (NO synthase cofactor) and that its replenishment would reprogram M2-TAMs to M1-TAMs. Recently, we reported that sepiapterin (SEP), the endogenous BH4 precursor, elevates the expression of M1- TAM markers within HER2+ tumors. Here, we show that SEP restores BH4 levels in M2-TAMs, which then redirects arginine metabolism to NO synthesis and converts M2-TAMs to M1-TAMs. The reprogrammed TAMs exhibit full-fledged capabilities of antigen presentation and induction of effector T cells to trigger immunogenic cell death of HER2+ cancer cells. This study substantiates the utility of SEP in metabolic shift of HER2+ breast tumor microenvironment as a novel immunotherapeutic strategy.

Reprogramming of breast tumor-associated macrophages with modulation of arginine metabolism

her2陽性乳がん腫瘍関連マクロファージのアルギニン代謝調節による再プログラミング


HER2陽性乳がん腫瘍関連マクロファージのアルギニン代謝調節による再プログラミング


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ZFP36L1はスーパーエンハンサーによって駆動され、IFN-γ誘導性のPD-L1発現を増強する。この機序は、ZFP36L1がHDAC3 mRNAの分解を促進することで実現される。


Gastric cancer (GC) is a major cause of cancer-related mortality worldwide. Despite the widespread recognition of tumor immunotherapy in treating unresectable GC, challenges, including ineffective immunotherapy and drug resistance, persist. Therefore, understanding the regulatory mechanisms of PD-L1, particularly in the context of super-enhancers (SEs) and zinc finger protein 36 ring finger protein-like 1 (ZFP36L1) RNA-binding protein, is crucial.

Methods In this study, we performed H3K27ac CUT&Tag sequencing, investigated the heterogeneity of SEs between two GC subtypes with differential growth patterns, and revealed the immune escape signatures driven by ZFP36L1-SE in infiltrative GC through SEs inhibitors treatment. The regulation of ZFP36L1 to PD-L1 was evaluated by quantitative PCR, western blot, flow cytometry and immunohistochemistry. Furthermore, we explored its regulatory mechanisms using a combination of molecular biology techniques, including luciferase reporter assay, GST/RNA pull-down, ChIP/RIP experiments, and in vivo functional assays.

Results We demonstrated that ZFP36L1, driven by an SE, enhances IFN-γ-induced PD-L1 expression, with SPI1 identified as the specific transcription factor binding to ZFP36L1-SE. Mechanistically, ZFP36L1 binds to the adenylate uridylate-rich element in the 3ʹUTR of HDAC3 mRNA, exacerbating its mRNA decay, and thereby facilitating PD-L1 abnormal transcriptional activation.

Conclusions Collectively, our findings provide mechanistic insights into the role of the SPI1– ZFP36L1–HDAC3–PD-L1 signaling axis in orchestrating immune escape mechanisms in GC, thereby offering valuable insights into the potential targets for immune checkpoint therapy in GC management.

### Competing Interest Statement

The authors have declared no competing interest.

*   3ʹUTR
    :   3ʹ untranslated region
    ARE
    :   adenylate uridylate rich element
    CTCF
    :   CCCTC-binding factor
    ER
    :   endoplasmic reticulum
    GC
    :   gastric cancer
    GO–KEGG
    :   Gene Ontology-Kyoto Encyclopedia of Genes and Genomes
    HDAC3
    :   Histone deacetylase 3
    IHC
    :   immunohistochemistry
    PD-L1
    :   programmed cell death-ligand-1
    ROSE
    :   ranking of SE
    SE
    :   Super-enhancers
    SNPs
    :   single nucleotide polymorphisms
    TCGA
    :   The Cancer Genome Atlas
    TIDE
    :   Tumor Immune Dysfunction and Exclusion
    TSS
    :   Transcription Start Site
    TTS
    :   Transcription Termination Site
    ZFP36L1
    :   zinc finger protein 36.

Super-enhancer-driven ZFP36L1 promotes PD-L1 expression in infiltrative gastric cancer

浸潤性胃がんにおけるスーパーエンハンサー駆動性zfp36l1によるpd-l1発現の促進


浸潤性胃がんにおけるスーパーエンハンサー駆動性ZFP36L1によるPD-L1発現の促進



がん患者の腫瘍内、リンパ節、末梢血のB細胞受容体レパートリーには大きな違いがあり、腫瘍微小環境がB細胞の発達と機能に大きな影響を及ぼしていることが示唆された。


The current understanding of humoral immune response in cancer patients suggests that tumors may be infiltrated with diffuse B cells of extra-tumoral origin or develop organized lymphoid structures, where somatic hypermutation and antigen-driven selection occur locally. These processes are thought to be significantly influenced by the tumor microenvironment in the form of secretory factors and biased cell-cell interactions. To address the manifestation of this influence, we used deep unbiased immunoglobulin profiling and systematically characterized the relationships between B cells in circulation, draining lymph nodes (draining LNs), and tumors in 14 patients with three human cancers. We show that draining LNs are differentially involved in the interaction with the tumor site and that there is significant heterogeneity even between different parts of a single lymph node (LN). Next, we confirmed and elaborated upon previous observations of intratumoral immunoglobulin heterogeneity. We identified B cell receptor (BCR) clonotypes that were expanded in tumors relative to draining LNs and blood and observed that these tumor-expanded clonotypes were less hypermutated than non-expanded (ubiquitous) clonotypes. Furthermore, we observed a shift in the properties of complementarity-determining region 3 of a BCR heavy chain (CDR-H3) towards less mature and less specific BCR repertoire in tumor-infiltrating B-cells compared to circulating B-cells, which may indicate less stringent control for antibody-producing B cell development in tumor microenvironment (TME). In addition, we found repertoire-level evidence that B-cells may be selected according to their CDR-H3 physicochemical properties before they activate somatic hypermutation (SHM). Altogether, our work outlines a broad picture of the difference in the tumor BCR repertoire relative to non-tumor tissues and points to the unexpected features of the SHM process.

### Competing Interest Statement

The authors have declared no competing interest.

*   (PBMC)
    :   Peripheral blood mononuclear cells
    (LN)
    :   lymph node
    ((tumor)-draining LNs)
    :   (tumor)-draining lymph nodes
    (BCR)
    :   B cell receptor
    (CDR-H3)
    :   complementarity-determining region 3 of a BCR heavy chain
    (TME)
    :   tumor microenvironment
    (SHM)
    :   somatic hypermutation
    (TLSs)
    :   tertiary lymphoid structures
    (TI-Bs)
    :   tumor-infiltrating B-cells
    (ADCC)
    :   antibody-dependent cytotoxicity
    (MDSC)
    :   myeloid-derived suppressor cells
    (LUAD)
    :   lung adenocarcinoma
    ( R apid A mplification of c DNA E nds)
    :   5’RACE
    (IGH)
    :   immunoglobulin heavy chain
    (SLE)
    :   systemic lupus erythematosus
    (CAR-T)
    :   chimeric antigen receptor T cell
    (MRCA)
    :   most recent common ancestor.

Systematic evaluation of intratumoral and peripheral BCR repertoires in three cancers

がんにおける腫瘍内および末梢bcr-レパートリーの体系的な評価


がんにおける腫瘍内および末梢BCR レパートリーの体系的な評価



尿路メラノーマ肝転移では、活性化、枯渇、および細胞傷害性の3つのサブタイプの腫瘍反応性T細胞が存在する。これらの細胞集団の特性化は、細胞療法の改善につながる可能性がある。


Uveal melanoma (UM) is a rare melanoma originating in the eye’s uvea, with 50% of patients experiencing metastasis predominantly in the liver. In contrast to cutaneous melanoma, there is only a limited effectiveness of combined immune checkpoint therapies, and half of patients succumb to recurrent disease after two years. This study aimed to provide a path towards enhancing immunotherapy efficacy by identifying and functionally validating tumor-reactive T cells in liver metastases of patients with UM. We employed single-cell RNA sequencing of biopsies and tumor-infiltrating lymphocytes (TILs) to identify potential tumor-reactive T cells. Patient-derived xenograft (PDX) models of UM metastases were created from patients, and tumor sphere cultures were generated from these models for co-culture with autologous or MART1-specific HLA-matched allogenic TILs. Activated T cells were subjected to TCR sequencing, and the TCRs were matched to those found in single-cell sequencing data from biopsies, expanded TILs and in livers or spleens of PDX models injected with TILs. Our findings revealed that tumor-reactive T cells resided not only among activated and exhausted subsets of T cells, but also in a subset of cytotoxic effector cells. In conclusion, combining single-cell sequencing and functional analysis provides valuable insights into which T cells in UM may be useful for cell therapy amplification and marker selection.

### Competing Interest Statement

The authors have declared no competing interest.

Patient-derived xenografts and single-cell sequencing identifies three subtypes of tumor-reactive lymphocytes in uveal melanoma metastases

肝転移を持つ尿路メラノーマ患者から単一細胞シーケンシングにより同定された3つのサブタイプの腫瘍反応性リンパ球


免疫原性細胞死関連遺伝子の発現レベルは膀胱がんの予後と免疫細胞浸潤に関連しており、リスクスコアリングモデルは患者の免疫環境、予後、免疫療法反応を評価する上で有用なツールとなる。


Immunogenic cell death (ICD) is a type of cell death sparking adaptive immune responses, can reshape the tumor microenvironment (TME). Exploring key ICD-related genes in bladder cancer (BLCA) could enhance personalized treatment. TCGA BLCA patients were divided into two ICD subtypes: ICD-high and ICD-low. High ICD expression linked to increased immune cell infiltration and longer survival, but with potentially suppressed immune function. The high ICD group responded better to PD1-targeted therapy. A risk-scoring model with four ICD-related genes (CALR, IL1R1, IFNB1, IFNG) was validated across TCGA, GEO datasets, and tissue samples, showing higher risk-score correlated with weaker anti-tumor immune function, more tumor-promoting elements, lower immunotherapy response rates, and shorter patient survival.This study connects ICD-related genes to BLCA prognosis and immune infiltration, offering a vital tool for personalized treatment guidance.

### Competing Interest Statement

The authors have declared no competing interest.

An Evaluation of the Tumor Microenvironment through CALR, IL1R1, IFNB1, and IFNG to Assess Prognosis and Immunotherapy Response in Bladder Cancer Patients

膀胱がん患者における予後と免疫療法反応を評価するためのcalr-il1r1-ifnb1-およびifngを介した腫瘍微小環境の評価


膀胱がん患者における予後と免疫療法反応を評価するためのCALR、IL1R1、IFNB1、およびIFNGを介した腫瘍微小環境の評価
