【Nature cancer】2024年2-5月刊论文导读

期刊介绍：

Nature Cancer创刊于2020年1月，是一本癌症领域期刊，旨在发表癌症生命、物理、应用和社会科学全方位研究的所有癌症研究中最重要的进展。从文章内容上看，Nature Cancer感兴趣的领域包括癌症生物学，癌症遗传学和基因组学，肿瘤进化和异质性，肿瘤微环境，肿瘤免疫学和免疫治疗，以及有助于研究，诊断，治疗和预防癌症的临床工作。在行业领域中学术影响力较大，属于JCR Q1，中科院1区SCI期刊，影响因子指数23.5。

2024年2月，第5卷第2期共发表14篇文章，其中1篇Comment & Opinion；3篇News & Views；2篇Research Briefings；1篇Reviews；7篇Research.

1.Cytokine-armed dendritic cell progenitors for antigen-agnostic cancer immunotherapy（封面文章）

细胞因子武装的树突状细胞前体用于抗原非特异性癌症免疫疗法

Abstract

Dendritic cells (DCs) are antigen-presenting myeloid cells that regulate T cell activation, trafficking and function. Monocyte-derived DCs pulsed with tumor antigens have been tested extensively for therapeutic vaccination in cancer, with mixed clinical results. Here, we present a cell-therapy platform based on mouse or human DC progenitors (DCPs) engineered to produce two immunostimulatory cytokines, IL-12 and FLT3L. Cytokine-armed DCPs differentiated into conventional type-I DCs (cDC1) and suppressed tumor growth, including melanoma and autochthonous liver models, without the need for antigen loading or myeloablative host conditioning. Tumor response involved synergy between IL-12 and FLT3L and was associated with natural killer and T cell infiltration and activation, M1-like macrophage programming and ischemic tumor necrosis. Antitumor immunity was dependent on endogenous cDC1 expansion and interferon-γ signaling but did not require CD8 T cell cytotoxicity. Cytokine-armed DCPs synergized effectively with anti-GD2 chimeric-antigen receptor (CAR) T cells in eradicating intracranial gliomas in mice, illustrating their potential in combination therapies.

摘要：

树突状细胞（DCs）是调节T细胞激活、迁移和功能的抗原呈递髓系细胞。过去的研究用肿瘤抗原脉冲处理后的单核细胞来源的DCs在癌症治疗性疫苗中进行了广泛的测试，但临床结果参差不齐。在这里，该研究介绍了一个基于小鼠或人类前体DC（DCPs）的细胞治疗平台，这些DCPs被编辑后可以产生两种免疫刺激性细胞因子：IL-12和FLT3L。经过细胞因子武装的DCPs在黑色素瘤和原发肝脏模型中可分化成常规的I型DCs（cDC1），并可以在不需要抗原加载或清髓性宿主预处理的情况下抑制肿瘤生长。肿瘤的响应涉及IL-12和FLT3L之间的协同作用，并与自然杀伤细胞和T细胞的浸润和激活、M1型巨噬细胞的编程和缺血性肿瘤坏死有关。抗肿瘤免疫依赖于内源性cDC1的扩增和干扰素γ信号，但不需要CD8+ T细胞的细胞毒性。另外，经过细胞因子武装的DCPs与抗GD2嵌合抗原受体（CAR）T细胞在消除小鼠颅内胶质瘤方面有效协同，展示了它们在联合治疗中的潜力。

2.LncRNA Malat1 suppresses pyroptosis and T cell-mediated killing of incipient metastatic cells

长链非编码RNA Malat1抑制细胞焦亡和T细胞介导的早期转移细胞的杀伤

Abstract

The contribution of antitumor immunity to metastatic dormancy is poorly understood. Here we show that the long noncoding RNA Malat1 is required for tumor initiation and metastatic reactivation in mouse models of breast cancer and other tumor types. Malat1 localizes to nuclear speckles to couple transcription, splicing and mRNA maturation. In metastatic cells, Malat1 induces WNT ligands, autocrine loops to promote self-renewal and the expression of Serpin protease inhibitors. Through inhibition of caspase-1 and cathepsin G, SERPINB6B prevents gasdermin D-mediated induction of pyroptosis. In this way, SERPINB6B suppresses immunogenic cell death and confers evasion of T cell-mediated tumor lysis of incipient metastatic cells. On-target inhibition of Malat1 using therapeutic antisense nucleotides suppresses metastasis in a SERPINB6B-dependent manner. These results suggest that Malat1-induced expression of SERPINB6B can titrate pyroptosis and immune recognition at metastatic sites. Thus, Malat1 is at the nexus of tumor initiation, reactivation and immune evasion and represents a tractable and clinically relevant drug target.

摘要：

抗肿瘤免疫对转移性休眠的贡献尚不清楚。在这里，该研究发现长非编码RNA Malat1在乳腺癌和其他肿瘤类型的小鼠模型中是肿瘤启动和转移再激活所必需的。Malat1定位于核斑，与转录、剪接和mRNA成熟相耦合。在转移细胞中，Malat1诱导WNT配体和自分泌环路以促进自我更新以及丝氨酸蛋白酶抑制剂的表达。通过抑制胱天蛋白酶1（caspase-1）和组织蛋白酶G（cathepsin G），SERPINB6B（一种丝氨酸蛋白酶抑制剂）阻止了由gasdermin D（细胞焦亡诱导剂）介导的焦亡（pyroptosis）。通过这种方式，SERPINB6B抑制了免疫原性细胞死亡，并赋予了初期转移细胞逃避T细胞介导的肿瘤溶解的能力。使用治疗性反义核苷酸靶向抑制Malat1，以SERPINB6B依赖的方式抑制了转移。这些结果表明，Malat1诱导的SERPINB6B表达可以在转移位点调节焦亡和免疫识别。因此，Malat1是肿瘤启动、再激活和免疫逃逸的关键点，并且是一个可行且具有临床相关性的药物靶标。

3.Autotaxin–lysolipid signaling suppresses a CCL11–eosinophil axis to promote pancreatic cancer progression

自分泌运动因子-溶血脂信号通路抑制CCL11-嗜酸性粒细胞轴，以促进胰腺癌的进展

Abstract

Lipids and their modifying enzymes regulate diverse features of the tumor microenvironment and cancer progression. The secreted enzyme autotaxin (ATX) hydrolyzes extracellular lysophosphatidylcholine to generate the multifunctional lipid mediator lysophosphatidic acid (LPA) and supports the growth of several tumor types, including pancreatic ductal adenocarcinoma (PDAC). Here we show that ATX suppresses the accumulation of eosinophils in the PDAC microenvironment. Genetic or pharmacologic ATX inhibition increased the number of intratumor eosinophils, which promote tumor cell apoptosis locally and suppress tumor progression. Mechanistically, ATX suppresses eosinophil accumulation via an autocrine feedback loop, wherein ATX–LPA signaling negatively regulates the activity of the AP-1 transcription factor c-Jun, in turn suppressing the expression of the potent eosinophil chemoattractant CCL11 (eotaxin-1). Eosinophils were identified in human PDAC specimens, and rare individuals with high intratumor eosinophil abundance had the longest overall survival. Together with recent findings, this study reveals the context-dependent, immune-modulatory potential of ATX–LPA signaling in cancer.

摘要：

脂质及其修饰酶能调控肿瘤微环境的多样性和癌症的进展。自分泌运动因子（ATX）通过水解细胞外溶血磷脂酰胆碱，产生多功能脂质介质-溶血磷脂酸（LPA），并支持包括胰腺导管腺癌（PDAC）在内的多种肿瘤类型的生长。在这里，该研究发现ATX能抑制PDAC微环境中嗜酸性粒细胞的积累。并且在基因或药理学上抑制ATX增加了肿瘤内嗜酸性粒细胞的数量，这些细胞可以促进局部肿瘤细胞凋亡并抑制肿瘤进展。从机制上讲，ATX通过自分泌反馈回路抑制嗜酸性粒细胞的积累，其中ATX-LPA信号传导负向调节AP-1转录因子c-Jun的活性，进而抑制强效嗜酸性粒细胞趋化因子CCL11（嗜酸性粒细胞趋化蛋白）的表达。另外，在人类PDAC样本中也鉴定出嗜酸性粒细胞，并且在肿瘤内嗜酸性粒细胞丰度高的少数个体观察到了最长的总生存期。结合最近的发现，这项研究揭示了ATX-LPA信号通路在癌症中的免疫调节潜力。

4.The Molecular Twin artificial-intelligence platform integrates multi-omic data to predict outcomes for pancreatic adenocarcinoma patients

Molecular Twin人工智能平台整合多组学数据来预测胰腺腺癌患者的结局

Abstract

Contemporary analyses focused on a limited number of clinical and molecular biomarkers have been unable to accurately predict clinical outcomes in pancreatic ductal adenocarcinoma. Here we describe a precision medicine platform known as the Molecular Twin consisting of advanced machine-learning models and use it to analyze a dataset of 6,363 clinical and multi-omic molecular features from patients with resected pancreatic ductal adenocarcinoma to accurately predict disease survival (DS). We show that a full multi-omic model predicts DS with the highest accuracy and that plasma protein is the top single-omic predictor of DS. A parsimonious model learning only 589 multi-omic features demonstrated similar predictive performance as the full multi-omic model. Our platform enables discovery of parsimonious biomarker panels and performance assessment of outcome prediction models learning from resource-intensive panels. This approach has considerable potential to impact clinical care and democratize precision cancer medicine worldwide.

摘要：

过去的研究主要集中在有限数量的临床和分子生物标志物上，无法准确预测出胰腺导管腺癌的临床结局。该研究开发了一个名为Molecular Twin的精准医疗平台，该平台由先进的机器学习模型组成，研究者使用它分析了一个包含6,363个胰腺导管腺癌切除的患者的临床和多组学分子特征的数据集，以准确预测疾病生存（DS）。结果发现，完整的多组学模型能以最高准确性来预测DS，并且发现血浆蛋白是DS的最佳单组学预测因子。一个仅使用589个多组学特征的简易模型表现出与完整多组学模型相似的预测性能。该平台能够发现简约的生物标记物面板，并评估从资源密集型面板中学习的结果预测模型的性能。该方法在影响临床护理和在全球范围内实现精准癌症医疗的普及方面具有相当大的潜力。

5.Somatic mouse models of gastric cancer reveal genotype-specific features of metastatic disease

胃癌的体细胞小鼠模型揭示了转移性疾病的基因型特异性特征

Abstract

Metastatic gastric carcinoma is a highly lethal cancer that responds poorly to conventional and molecularly targeted therapies. Despite its clinical relevance, the mechanisms underlying the behavior and therapeutic response of this disease are poorly understood owing, in part, to a paucity of tractable models. Here we developed methods to somatically introduce different oncogenic lesions directly into the murine gastric epithelium. Genotypic configurations observed in patients produced metastatic gastric cancers that recapitulated the histological, molecular and clinical features of all nonviral molecular subtypes of the human disease. Applying this platform to both wild-type and immunodeficient mice revealed previously unappreciated links between the genotype, organotropism and immune surveillance of metastatic cells, which produced distinct patterns of metastasis that were mirrored in patients. Our results establish a highly portable platform for generating autochthonous cancer models with flexible genotypes and host backgrounds, which can unravel mechanisms of gastric tumorigenesis or test new therapeutic concepts.

摘要：

转移性胃癌是一种高度致命的癌症，对传统疗法和分子靶向治疗反应较差。尽管其临床相关性很高，但由于缺乏适用的研究模型，该疾病的行为机制及其对治疗的反应仍然知之甚少。在本研究中，我们开发了一种方法，可以将不同的致癌病变直接引入小鼠的胃上皮组织中。患者中观察到的基因型配置生成了转移性胃癌，并且再现了人类疾病中所有非病毒分子亚型的组织学、分子和临床特征。将这一平台应用于野生型和免疫缺陷小鼠的实验中，揭示了此前未被认识到的基因型、器官趋向性以及转移细胞免疫监视之间的关联，这些关系在患者中表现出类似的转移模式。我们的研究成果建立了一个高度便携的平台，可以生成具有灵活基因型和宿主背景的原位癌模型，从而揭示胃癌发生的机制或用于测试新的治疗理念。

6.Cell cycle gene alterations associate with a redistribution of mutation risk across chromosomal domains in human cancers

细胞周期的基因改变与人类癌症染色体结构域之间突变风险的重新分布有关

Abstract

Mutations in human cells exhibit increased burden in heterochromatic, late DNA replication time (RT) chromosomal domains, with variation in mutation rates between tissues mirroring variation in heterochromatin and RT. We observed that regional mutation risk further varies between individual tumors in a manner independent of cell type, identifying three signatures of domain-scale mutagenesis in >4,000 tumor genomes. The major signature reflects remodeling of heterochromatin and of the RT program domains seen across tumors, tissues and cultured cells, and is robustly linked with higher expression of cell proliferation genes. Regional mutagenesis is associated with loss of activity of the tumor-suppressor genes RB1 and TP53, consistent with their roles in cell cycle control, with distinct mutational patterns generated by the two genes. Loss of regional heterogeneity in mutagenesis is associated with deficiencies in various DNA repair pathways. These mutation risk redistribution processes modify the mutation supply towards important genes, diverting the course of somatic evolution.

摘要：

在人类细胞中，突变负担在异染色质区域和晚期DNA复制时间（RT）的染色体域显著增加，不同组织间的突变率差异反映了异染色质和RT的变化。该研究观察到，在不同个体肿瘤间，这些区域的突变风险也会发生变化，且这种变化与细胞类型无关。在超过4000个肿瘤基因组中，研究者鉴定出了三种染色质域尺度的突变特征。主要特征反映了跨肿瘤、组织和培养细胞的异染色质和RT程序域的重塑，并且这一特征与细胞增殖基因的高表达密切相关。区域性突变与肿瘤抑制基因RB1和TP53的活性丧失有关，这与它们在细胞周期控制中的作用一致，并且这两个基因产生了不同的突变模式。区域突变异质性的丧失与多种DNA修复途径的缺陷有关。这些突变风险重新分配的过程改变了重要基因的突变方向，进而改变了体细胞进化的进程。

7.The artificial intelligence-based model ANORAK improves histopathological grading of lung adenocarcinoma

基于人工智能的模型ANORAK改善了肺腺癌的组织病理分级

Abstract

The introduction of the International Association for the Study of Lung Cancer grading system has furthered interest in histopathological grading for risk stratification in lung adenocarcinoma. Complex morphology and high intratumoral heterogeneity present challenges to pathologists, prompting the development of artificial intelligence (AI) methods. Here we developed ANORAK (pyrAmid pooliNg crOss stReam Attention networK), encoding multiresolution inputs with an attention mechanism, to delineate growth patterns from hematoxylin and eosin-stained slides. In 1,372 lung adenocarcinomas across four independent cohorts, AI-based grading was prognostic of disease-free survival, and further assisted pathologists by consistently improving prognostication in stage I tumors. Tumors with discrepant patterns between AI and pathologists had notably higher intratumoral heterogeneity. Furthermore, ANORAK facilitates the morphological and spatial assessment of the acinar pattern, capturing acinus variations with pattern transition. Collectively, our AI method enabled the precision quantification and morphology investigation of growth patterns, reflecting intratumoral histological transitions in lung adenocarcinoma.

摘要

国际肺癌研究协会（IASLC）分级系统的引入，进一步激发了人们对肺腺癌风险分层中组织病理分级的兴趣。然而，复杂的形态学特征和高度的肿瘤内异质性给病理学家们带来了挑战，这促使了人工智能(Artificial Intelligence, AI)方法的开发。在这里，该研究开发了一个名为ANORAK（pyramid pooliNg crOss stReam Attention networK）的系统，它利用注意力机制对多分辨率输入编码，从苏木精-伊红染色的切片中解析肿瘤生长模式。在四个独立队列的1372例肺腺癌中，基于AI的分级能够预测无病生存期，并且在I期肿瘤中能提高预后评估，辅助病理学家的工作。AI和病理学家在肿瘤生长模式识别上存在差异的肿瘤，通常表现出更高的肿瘤内异质性。此外，ANORAK还促进了腺泡模式的形态学和空间评估，捕捉了伴随模式转换的腺泡变化。总体而言，该研究的AI方法实现了生长模式的精确量化和形态学研究，反映了肺腺癌肿瘤内的组织学转变。

2024年3月，第5卷第3期共发表16篇文章，其中1篇Turning Points；1篇Comment & Opinion；3篇News & Views；2篇Research Briefings；1篇Review Articles；8篇Articles。

1.PD-1 defines a distinct, functional, tissue-adapted state in Vδ1+ T cells with implications for cancer immunotherapy（封面文章）

PD-1定义了一种独特的、功能性的、适应组织的Vδ1+ T细胞状态，这对癌症免疫疗法具有重要意义

Abstract

Checkpoint inhibition (CPI), particularly that targeting the inhibitory coreceptor programmed cell death protein 1 (PD-1), has transformed oncology. Although CPI can derepress cancer (neo)antigen-specific αβ T cells that ordinarily show PD-1-dependent exhaustion, it can also be efficacious against cancers evading αβ T cell recognition. In such settings, γδ T cells have been implicated, but the functional relevance of PD-1 expression by these cells is unclear. Here we demonstrate that intratumoral TRDV1 transcripts (encoding the TCRδ chain of Vδ1+ γδ T cells) predict anti-PD-1 CPI response in patients with melanoma, particularly those harboring below average neoantigens. Moreover, using a protocol yielding substantial numbers of tissue-derived Vδ1+ cells, we show that PD-1+Vδ1+ cells display a transcriptomic program similar to, but distinct from, the canonical exhaustion program of colocated PD-1+CD8+ αβ T cells. In particular, PD-1+Vδ1+ cells retained effector responses to TCR signaling that were inhibitable by PD-1 engagement and derepressed by CPI.

摘要

检查点抑制（CPI），特别是针对抑制性共受体程序性细胞死亡蛋白1（PD-1）的治疗，已经彻底改变了肿瘤学领域。虽然CPI能够解除PD-1依赖性耗竭的癌症（新）抗原特异性αβT细胞的抑制作用，但它也能够对抗那些逃避αβT细胞识别的癌症。在这种情况下，有研究认为γδ T细胞在其中发挥了作用，但这些细胞表达PD-1的功能意义尚不清楚。在这里，该研究发现肿瘤内部TRDV1基因转录本（编码Vδ1+γδT细胞的TCRδ链）能够预测黑色素瘤患者对抗PD-1 CPI治疗的反应，特别是那些新抗原数量低于平均水平的患者。此外，通过一种能够产生大量组织来源Vδ1+细胞的方法，研究发现PD-1+ Vδ1+细胞显示出与PD-1+ CD8+αβT细胞的经典耗竭程序相似但又不同的转录组程序。特别是，PD-1+ Vδ1+细胞保留了对TCR信号的效应反应，这些反应能够被PD-1的结合抑制，并且能够被CPI治疗解除抑制。

2.Inhibition of ADAM9 promotes the selective degradation of KRAS and sensitizes pancreatic cancers to chemotherapy

抑制ADAM9促进KRAS的选择性降解，并使胰腺癌对化疗更加敏感

Abstract

Kirsten rat sarcoma virus (KRAS) signaling drives pancreatic ductal adenocarcinoma (PDAC) malignancy, which is an unmet clinical need. Here, we identify a disintegrin and metalloproteinase domain (ADAM)9 as a modulator of PDAC progression via stabilization of wild-type and mutant KRAS proteins. Mechanistically, ADAM9 loss increases the interaction of KRAS with plasminogen activator inhibitor 1 (PAI-1), which functions as a selective autophagy receptor in conjunction with light chain 3 (LC3), triggering lysosomal degradation of KRAS. Suppression of ADAM9 by a small-molecule inhibitor restricts disease progression in spontaneous models, and combination with gemcitabine elicits dramatic regression of patient-derived tumors. Our findings provide a promising strategy to target the KRAS signaling cascade and demonstrate a potential modality to enhance sensitivity to chemotherapy in PDAC.

摘要

KRAS信号通路驱动胰腺导管腺癌（PDAC）的恶性进展，但目前还没有针对该通路的有效治疗策略。在这里，该研究发现ADAM9是PDAC进展的调节因子，它通过稳定野生型和突变型KRAS蛋白来调节PDAC的进展。从机制上讲，ADAM9的缺失增加了KRAS与纤溶酶原激活剂抑制剂1（PAI-1）的相互作用，PAI-1作为选择性自噬受体与轻链3（LC3）一起发挥作用，触发KRAS的溶酶体降解。小分子抑制剂抑制ADAM9能在自发模型中限制疾病进展，并且与吉西他滨联合使用能显著抑制患者肿瘤的生长。该研究结果提供了一种很有前景的方法来靶向KRAS信号级联反应，并提出了一种提高PDAC化疗敏感性的潜在方法。

3.Loss of Pip4k2c confers liver-metastatic organotropism through insulin-dependent PI3K-AKT pathway activation

Pip4k2c基因的丢失通过胰岛素依赖的PI3K-AKT途径的激活，赋予了肝脏转移性器官特异性

Abstract

Liver metastasis (LM) confers poor survival and therapy resistance across cancer types, but the mechanisms of liver-metastatic organotropism remain unknown. Here, through in vivo CRISPR–Cas9 screens, we found that Pip4k2c loss conferred LM but had no impact on lung metastasis or primary tumor growth. Pip4k2c-deficient cells were hypersensitized to insulin-mediated PI3K/AKT signaling and exploited the insulin-rich liver milieu for organ-specific metastasis. We observed concordant changes in PIP4K2C expression and distinct metabolic changes in 3,511 patient melanomas, including primary tumors, LMs and lung metastases. We found that systemic PI3K inhibition exacerbated LM burden in mice injected with Pip4k2c-deficient cancer cells through host-mediated increase in hepatic insulin levels; however, this circuit could be broken by concurrent administration of an SGLT2 inhibitor or feeding of a ketogenic diet. Thus, this work demonstrates a rare example of metastatic organotropism through co-optation of physiological metabolic cues and proposes therapeutic avenues to counteract these mechanisms.

摘要

肝脏转移（LM）在各种癌症类型中都预示着较差的生存率和治疗抵抗性，但肝脏转移的器官特异性的机制仍然未知。在这里，通过体内CRISPR-Cas9筛选，该研究发现Pip4k2c基因的丢失会促进肝脏转移，但对肺转移或原发肿瘤生长没有影响。Pip4k2c缺陷细胞对胰岛素介导的PI3K/AKT信号通路高度敏感，并利用富含胰岛素的肝脏环境进行器官特异性转移。我们在3511例黑色素瘤患者（包括原发肿瘤、肝脏转移和肺转移）的肿瘤中观察到PIP4K2C表达的一致变化及不同代谢变化。研究者还发现，系统性PI3K抑制会通过宿主介导的肝脏胰岛素水平升高，加重注射了Pip4k2c缺陷癌细胞的小鼠的肝转移负担；然而，这一回路可以通过同时给予SGLT2抑制剂或生酮饮食来中断。因此，这项工作发现了一个通过生理代谢信号导致器官转移趋向性的罕见例子，并提出了对抗这些机制的治疗途径。

4.The efficacy of chemotherapy is limited by intratumoral senescent cells expressing PD-L2

化疗的疗效受到表达PD-L2的肿瘤内衰老细胞的限制

Abstract

Chemotherapy often generates intratumoral senescent cancer cells that strongly modify the tumor microenvironment, favoring immunosuppression and tumor growth. We discovered, through an unbiased proteomics screen, that the immune checkpoint inhibitor programmed cell death 1 ligand 2 (PD-L2) is highly upregulated upon induction of senescence in different types of cancer cells. PD-L2 is not required for cells to undergo senescence, but it is critical for senescent cells to evade the immune system and persist intratumorally. Indeed, after chemotherapy, PD-L2-deficient senescent cancer cells are rapidly eliminated and tumors do not produce the senescence-associated chemokines CXCL1 and CXCL2. Accordingly, PD-L2-deficient pancreatic tumors fail to recruit myeloid-derived suppressor cells and undergo regression driven by CD8 T cells after chemotherapy. Finally, antibody-mediated blockade of PD-L2 strongly synergizes with chemotherapy causing remission of mammary tumors in mice. The combination of chemotherapy with anti-PD-L2 provides a therapeutic strategy that exploits vulnerabilities arising from therapy-induced senescence

摘要

化疗常常在肿瘤内产生衰老的癌细胞，这些细胞会显著改变肿瘤微环境，促进免疫抑制和肿瘤生长。该研究通过一个无偏倚蛋白质组学筛选发现，免疫检查点抑制剂程序性细胞死亡蛋白配体2（PD-L2）在不同类型的癌细胞中当细胞衰老时高度上调。PD-L2对于细胞进入衰老状态并非必需，但对于衰老细胞逃避免疫系统并在肿瘤内持续存在至关重要。事实上，在化疗后，缺乏PD-L2的衰老癌细胞会迅速被清除，肿瘤也不会产生与衰老相关的趋化因子CXCL1和CXCL2。相应地，缺乏PD-L2的胰腺肿瘤无法招募骨髓来源的抑制细胞，并且在化疗后会通过CD8 T细胞的驱动发生肿瘤退行。最后，研究发现，抗体介导的PD-L2阻断与化疗联合能产生强烈的协同作用，在小鼠中实现乳腺肿瘤的缓解。将化疗与抗PD-L2相结合，提供了一种利用由治疗诱导的细胞衰老的治疗策略。

5.The dopamine transporter antagonist vanoxerine inhibits G9a and suppresses cancer stem cell functions in colon tumors

多巴胺转运体拮抗剂伐诺司林（vanoxerine）抑制G9a并抑制结肠肿瘤中癌症干细胞的功能

Abstract

Cancer stem cells (CSCs), functionally characterized by self-renewal and tumor-initiating activity, contribute to decreased tumor immunogenicity, while fostering tumor growth and metastasis. Targeting G9a histone methyltransferase (HMTase) effectively blocks CSC functions in colorectal tumors by altering pluripotent-like molecular networks; however, existing molecules directly targeting G9a HMTase activity failed to reach clinical stages due to safety concerns. Using a stem cell-based phenotypic drug-screening pipeline, we identified the dopamine transporter (DAT) antagonist vanoxerine, a compound with previously demonstrated clinical safety, as a cancer-specific downregulator of G9a expression. Here we show that gene silencing and chemical antagonism of DAT impede colorectal CSC functions by repressing G9a expression. Antagonizing DAT also enhanced tumor lymphocytic infiltration by activating endogenous transposable elements and type-I interferon response. Our study unveils the direct implication of the DAT–G9a axis in the maintenance of CSC populations and an approach to improve antitumor immune response in colon tumors.

摘要

癌症干细胞（CSCs）有自我更新和肿瘤起始活性的功能，不仅降低了肿瘤免疫原性，同时还促进肿瘤生长和转移。过去的研究发现，靶向G9a组蛋白甲基转移酶（HMTase）能通过改变多能性分子网络，有效阻断结直肠肿瘤中CSC的功能；然而，由于安全问题，现有的直接靶向G9a HMTase活性的分子未能进入临床试验阶段。通过干细胞表型药物筛选流程，该研究团队筛选出了多巴胺转运体（DAT）拮抗剂伐诺司林，这是一种已被证明具有临床安全性的化合物，能特异性地下调癌细胞中G9a的表达。在本研究中，研究者发现基因沉默和化学拮抗DAT可以通过抑制G9a的表达阻碍结直肠CSC的功能。此外，拮抗DAT还通过激活内源性转座子和I型干扰素反应来增强肿瘤淋巴细胞浸润。总之，该研究揭示了DAT-G9a轴在维持CSC群体中的直接作用，并提出了一种改善结肠癌肿瘤抗免疫反应的方法。

6.INPP5A phosphatase is a synthetic lethal target in GNAQ and GNA11-mutant melanomas

INPP5A磷酸酶是GNAQ和GNA11突变型黑色素瘤中的合成致死靶点

Abstract

Activating mutations in GNAQ/GNA11 occur in over 90% of uveal melanomas (UMs), the most lethal melanoma subtype; however, targeting these oncogenes has proven challenging and inhibiting their downstream effectors show limited clinical efficacy. Here, we performed genome-scale CRISPR screens along with computational analyses of cancer dependency and gene expression datasets to identify the inositol-metabolizing phosphatase INPP5A as a selective dependency in GNAQ/11-mutant UM cells in vitro and in vivo. Mutant cells intrinsically produce high levels of the second messenger inositol 1,4,5 trisphosphate (IP3) that accumulate upon suppression of INPP5A, resulting in hyperactivation of IP3-receptor signaling, increased cytosolic calcium and p53-dependent apoptosis. Finally, we show that GNAQ/11-mutant UM cells and patients’ tumors exhibit elevated levels of IP4, a biomarker of enhanced IP3 production; these high levels are abolished by GNAQ/11 inhibition and correlate with sensitivity to INPP5A depletion. Our findings uncover INPP5A as a synthetic lethal vulnerability and a potential therapeutic target for GNAQ/11-mutant-driven cancers.

摘要

GNAQ/GNA11的激活突变在超过90%的葡萄膜黑色素瘤（UMs）中发生，这是一种最致命的UM亚型。然而，针对这些癌基因的治疗一直具有挑战性，且抑制它们下游效应子的临床效果十分有限。在这里，该研究进行了全基因组CRISPR筛选，并结合癌症依赖性和基因表达数据集的计算分析，识别出肌醇代谢磷酸酶INPP5A是GNAQ/11突变型UM细胞在体外和体内的选择性依赖性靶点。突变细胞本质上会产生高水平的第二信使肌醇1,4,5三磷酸（IP3），当INPP5A被抑制时这些IP3会积累，导致IP3受体信号过度激活，细胞质内钙离子增加，以及p53依赖性细胞凋亡。最后，研究展示了GNAQ/11突变型UM细胞和患者肿瘤表现出IP4水平升高，IP4是IP3产生增强的生物标志物；这些高水平的IP4在GNAQ/11抑制后被消除，并与对INPP5A耗竭的敏感性相关。总之，该研究的发现揭示了INPP5A作为一个合成致死脆弱性分子的作用，并提出INPP5A可以作为GNAQ/11突变驱动癌症的潜在治疗靶点。

7.Sirpα on tumor-associated myeloid cells restrains antitumor immunity in colorectal cancer independent of its interaction with CD47

肿瘤相关髓系细胞上的SIRPα独立于其与CD47的相互作用，抑制了结直肠癌中的抗肿瘤免疫反应

Abstract

Immunosuppressive myeloid cells hinder immunotherapeutic efficacy in tumors, but the precise mechanisms remain undefined. Here, by performing single-cell RNA sequencing in colorectal cancer tissues, we found tumor-associated macrophages and granulocytic myeloid-derived suppressor cells increased most compared to their counterparts in normal tissue and displayed the highest immune-inhibitory signatures among all immunocytes. These cells exhibited significantly increased expression of immunoreceptor tyrosine-based inhibitory motif-bearing receptors, including SIRPA. Notably, Sirpa−/− mice were more resistant to tumor progression than wild-type mice. Moreover, Sirpα deficiency reprogramed the tumor microenvironment through expansion of TAM_Ccl8hi and gMDSC_H2-Q10hi subsets showing strong antitumor activity. Sirpa−/− macrophages presented strong phagocytosis and antigen presentation to enhance T cell activation and proliferation. Furthermore, Sirpa−/− macrophages facilitated T cell recruitment via Syk/Btk-dependent Ccl8 secretion. Therefore, Sirpα deficiency enhances innate and adaptive immune activation independent of expression of CD47 and Sirpα blockade could be a promising strategy to improve cancer immunotherapy efficacy.

摘要

免疫抑制性髓系细胞会阻碍肿瘤免疫治疗的效果，但确切的机制尚不明确。在这里，通过对结直肠癌组织进行单细胞RNA测序，研究者发现与正常组织相比，肿瘤相关巨噬细胞和粒细胞样髓系来源的抑制细胞（MDSCs）数量显著增加，并且在所有免疫细胞中显示出最强的免疫抑制特征。这些细胞显著上调了免疫受体酪氨酸抑制性基序（ITIM）受体（包括SIRPα）的表达。值得注意的是，SIRPA基因敲除（Sirpa−/−）小鼠相比于野生型小鼠对肿瘤进展表现出更强的抵抗力。此外，SIRPα缺乏通过扩增表现出强烈抗肿瘤活性的TAM_Ccl8hi和gMDSC_H2-Q10hi亚群进而重塑了肿瘤微环境。SIRPA基因敲除的巨噬细胞表现出强大的吞噬作用和抗原呈递能力，从而促进了T细胞的激活和增殖。此外，SIRPA基因敲除的巨噬细胞通过Syk/Btk（信号转导途径）依赖的Ccl8（趋化因子）分泌促进了T细胞的募集。因此，SIRPα的缺失能增强先天和适应性免疫的活性，这种激活独立于CD47的表达，阻断SIRPα可能是一种提高癌症免疫治疗效果的有前景的策略。

8.Repeated peripheral infusions of anti-EGFRvIII CAR T cells in combination with pembrolizumab show no efficacy in glioblastoma: a phase 1 trial

在胶质母细胞瘤中，重复外周输注抗EGFRvIII CAR T细胞与派姆单抗（pembrolizumab）联合使用未显示出疗效：一项1期临床试验

Abstract

We previously showed that chimeric antigen receptor (CAR) T-cell therapy targeting epidermal growth factor receptor variant III (EGFRvIII) produces upregulation of programmed death-ligand 1 (PD-L1) in the tumor microenvironment (TME). Here we conducted a phase 1 trial (NCT03726515) of CAR T-EGFRvIII cells administered concomitantly with the anti-PD1 (aPD1) monoclonal antibody pembrolizumab in patients with newly diagnosed, EGFRvIII+ glioblastoma (GBM) (n = 7). The primary outcome was safety, and no dose-limiting toxicity was observed. Secondary outcomes included median progression-free survival (5.2 months; 90% confidence interval (CI), 2.9–6.0 months) and median overall survival (11.8 months; 90% CI, 9.2–14.2 months). In exploratory analyses, comparison of the TME in tumors harvested before versus after CAR + aPD1 administration demonstrated substantial evolution of the infiltrating myeloid and T cells, with more exhausted, regulatory, and interferon (IFN)-stimulated T cells at relapse. Our study suggests that the combination of CAR T cells and PD-1 inhibition in GBM is safe and biologically active but, given the lack of efficacy, also indicates a need to consider alternative strategies

摘要

之前的研究表明，靶向表皮生长因子受体变体III（EGFRvIII）的嵌合抗原受体T细胞疗法（CAR-T）可以在肿瘤微环境（TME）中引起程序性死亡配体1（PD-L1）的上调。在这里，该研究进行了一项1期临床试验（NCT03726515）：在新诊断的、EGFRvIII阳性的胶质母细胞瘤（GBM）患者（n=7）中，联合使用CAR T-EGFRvIII细胞和抗PD-1（aPD1）单克隆抗体派姆单抗。主要结局是安全性，没有观察到剂量限制性毒性。次要结果包括中位无进展生存期（5.2个月；90%置信区间（CI），2.9-6.0个月）和中位总生存期（11.8个月；90% CI，9.2-14.2个月）。在探索性分析中，对比CAR + aPD1治疗前后的TME，显示浸润性髓系细胞和T细胞发生了显著变化，复发时有更多的耗竭性、调节性和干扰素（IFN）-刺激的T细胞。总之，该研究表明，CAR-T细胞和PD-1抑制剂在GBM中的联合使用是安全的并且具有生物学活性，但鉴于疗效不足，提示需要考虑替代的治疗策略。

2024年4月，第5卷第4期共发表16篇文章，其中3篇News & Views；2篇Research Briefings；2篇Reviews；3篇Research Briefings；7篇Articles；2篇Amendments & Corrections。

1.Integrated multiomic profiling of breast cancer in the Chinese population reveals patient stratification and therapeutic vulnerabilities（封面文章）

对中国人群中乳腺癌的综合多组学分析揭示了患者的分层和治疗脆弱性

Abstract

Molecular profiling guides precision treatment of breast cancer; however, Asian patients are underrepresented in publicly available large-scale studies. We established a comprehensive multiomics cohort of 773 Chinese patients with breast cancer and systematically analyzed their genomic, transcriptomic, proteomic, metabolomic, radiomic and digital pathology characteristics. Here we show that compared to breast cancers in white individuals, Asian individuals had more targetable AKT1 mutations. Integrated analysis revealed a higher proportion of HER2-enriched subtype and correspondingly more frequent ERBB2 amplification and higher HER2 protein abundance in the Chinese HR+HER2+ cohort, stressing anti-HER2 therapy for these individuals. Furthermore, comprehensive metabolomic and proteomic analyses revealed ferroptosis as a potential therapeutic target for basal-like tumors. The integration of clinical, transcriptomic, metabolomic, radiomic and pathological features allowed for efficient stratification of patients into groups with varying recurrence risks. Our study provides a public resource and new insights into the biology and ancestry specificity of breast cancer in the Asian population, offering potential for further precision treatment approaches.

摘要

分子分型可以指导乳腺癌的精准治疗，然而，在公开可用的大规模研究中，亚洲患者代表性不足。因此，该研究建立了一个包含773名中国乳腺癌患者的综合多组学队列，并系统分析了他们的基因组、转录组、蛋白质组、代谢组、影像组学和数字病理特征。结果发现，与白人个体的乳腺癌相比，亚洲个体中有更多可靶向的AKT1突变。综合分析显示，在中国的HR+ HER2+队列中，HER2富集亚型的比例更高，相应地ERBB2扩增更频繁，HER2蛋白含量更高，这强调了对这些个体进行抗HER2治疗的重要性。此外，全面的代谢组和蛋白质组分析显示，铁死亡可以作为基底样肿瘤的潜在治疗靶点。将临床、转录组、代谢组、影像组和病理特征的整合，高效地将患者分为不同复发风险的组别。总之，该研究提为亚洲人群中乳腺癌的生物学和种族特异性提供了公共资源和新的见解，为进一步的精准治疗提供了可能性。

2.Targeted activation of ferroptosis in colorectal cancer via LGR4 targeting overcomes acquired drug resistance

通过LGR4靶向激活结直肠癌中的铁死亡以克服获得性耐药

Abstract

Acquired drug resistance is a major challenge for cancer therapy and is the leading cause of cancer mortality; however, the mechanisms of drug resistance are diverse and the strategy to specifically target drug-resistant cancer cells remains an unmet clinical issue. Here, we established a colorectal cancer-derived organoid biobank and induced acquired drug resistance by repeated low-level exposures of chemo-agents. Chemosensitivity profiling and transcriptomic analysis studies revealed that chemoresistant cancer-derived organoids exhibited elevated expression of LGR4 and activation of the Wnt signaling pathway. Further, we generated a monoclonal antibody (LGR4-mAb) that potently inhibited LGR4–Wnt signaling and found that treatment with LGR4-mAb notably sensitized drug-induced ferroptosis. Mechanistically, LGR4-dependent Wnt signaling transcriptionally upregulated SLC7A11, a key inhibitor of ferroptosis, to confer acquired drug resistance. Our findings reveal that targeting of Wnt signaling by LGR4-mAb augments ferroptosis when co-administrated with chemotherapeutic agents, demonstrating a potential opportunity to fight refractory and recurrent cancers.

摘要

获得性耐药性是癌症治疗的主要挑战，也是癌症死亡的主要原因。然而，耐药性的机制多样，且如何特异性靶向耐药癌细胞仍然是一个未解决的临床问题。在这里，该研究建立了一个结直肠癌衍生的类器官生物库，并通过反复低剂量的化学药物暴露来诱导获得性耐药性。化学敏感性分析和转录组学研究显示，耐药癌细胞来源的类器官表现出LGR4表达上调和Wnt信号通路的激活。研究进一步合成了一种单克隆抗体（LGR4-mAb），它能有效抑制LGR4-Wnt信号，并且用LGR4-mAb治疗能促进药物诱导的铁死亡。从机制上讲，LGR4依赖的Wnt信号通过转录上调了铁死亡的关键抑制因子SLC7A11的表达，从而赋予癌细胞获得性耐药性。总之，该研究的结果表明，当与化疗药物共同给药时，LGR4-mAb靶向Wnt信号通路会增强癌细胞铁死亡，这为对抗难治性和复发性癌症提供了潜在的治疗机会。

3.Temporal changes in treatment and late mortality and morbidity in adult survivors of childhood glioma: a report from the Childhood Cancer Survivor Study

儿童胶质瘤成年幸存者治疗的时间变化及其晚期死亡率和发病率：来自儿童癌症幸存者研究的报告

Abstract

Pediatric glioma therapy has evolved to delay or eliminate radiation for low-grade tumors. This study examined these temporal changes in therapy with long-term outcomes in adult survivors of childhood glioma. Among 2,501 5-year survivors of glioma in the Childhood Cancer Survivor Study diagnosed 1970–1999, exposure to radiation decreased over time. Survivors from more recent eras were at lower risk of late mortality (≥5 years from diagnosis), severe/disabling/life-threatening chronic health conditions (CHCs) and subsequent neoplasms (SNs). Adjusting for treatment exposure (surgery only, chemotherapy, or any cranial radiation) attenuated this risk (for example, CHCs (1990s versus 1970s), relative risk (95% confidence interval), 0.63 (0.49–0.80) without adjustment versus 0.93 (0.72–1.20) with adjustment). Compared to surgery alone, radiation was associated with greater than four times the risk of late mortality, CHCs and SNs. Evolving therapy, particularly avoidance of cranial radiation, has improved late outcomes for childhood glioma survivors without increased risk for late recurrence.

摘要

儿童胶质瘤的治疗方法已经演变，对于低级别肿瘤，现在倾向于推迟或消除放射治疗。。本研究探讨了儿童胶质瘤成年幸存者中治疗中的时间变化及其长期结果。在1970-1999年间确诊的儿童癌症幸存者研究中，有2501名胶质瘤的5年幸存者，随时间推移，他们接受放射治疗的比例逐渐变小。另外，近年来的幸存者在晚期死亡率（诊断后≥5年）、严重/致残/危及生命的慢性健康状况（CHCs）和继发性肿瘤（SNs）方面的发生风险较低。调整治疗暴露（仅手术、化疗或任何颅脑放疗）后，这种风险有所减弱（例如，未调整时1990年代与1970年代相比的CHCs相对风险（95%置信区间），0.63（0.49–0.80）与调整后的0.93（0.72–1.20））。与单纯手术相比，放疗患者发生晚期死亡、CHCs和SNs的风险高出四倍以上。总之，随着治疗方式的演变，特别是避免颅脑放疗，改善了儿童胶质瘤幸存者的晚期结局，并且没有增加晚期复发的风险。

4.Targeting PRMT9-mediated arginine methylation suppresses cancer stem cell maintenance and elicits cGAS-mediated anticancer immunity

靶向PRMT9介导的精氨酸甲基化抑制了癌症干细胞的维持，并激发了cGAS介导的抗癌免疫

Abstract

Current anticancer therapies cannot eliminate all cancer cells, which hijack normal arginine methylation as a means to promote their maintenance via unknown mechanisms. Here we show that targeting protein arginine N-methyltransferase 9 (PRMT9), whose activities are elevated in blasts and leukemia stem cells (LSCs) from patients with acute myeloid leukemia (AML), eliminates disease via cancer-intrinsic mechanisms and cancer-extrinsic type I interferon (IFN)-associated immunity. PRMT9 ablation in AML cells decreased the arginine methylation of regulators of RNA translation and the DNA damage response, suppressing cell survival. Notably, PRMT9 inhibition promoted DNA damage and activated cyclic GMP-AMP synthase, which underlies the type I IFN response. Genetically activating cyclic GMP-AMP synthase in AML cells blocked leukemogenesis. We also report synergy of a PRMT9 inhibitor with anti-programmed cell death protein 1 in eradicating AML. Overall, we conclude that PRMT9 functions in survival and immune evasion of both LSCs and non-LSCs; targeting PRMT9 may represent a potential anticancer strategy.

摘要

目前的抗癌疗法无法消灭所有癌细胞，这些癌细胞通过未知的机制劫持了正常的精氨酸甲基化，以促进自身的存活。在这里，该研究发现靶向蛋白精氨酸N-甲基转移酶9（PRMT9），能通过癌细胞内在的机制和癌症外在的I型干扰素（IFN）相关免疫来消除疾病。PRMT9在急性髓系白血病（AML）患者的白血病母细胞和白血病干细胞（LSCs）中的活性升高。在AML细胞中，PRMT9的敲除降低了RNA翻译和DNA损伤反应调节因子的精氨酸甲基化，抑制了细胞存活。值得注意的是，PRMT9的抑制促进了DNA损伤并激活了环状GMP-AMP合成酶（cGAS），这是I型IFN反应的基础。通过基因编辑的方式在AML细胞中激活cGAS可以阻止白血病的发生。此外，研究还报告了PRMT9抑制剂与抗程序性细胞死亡蛋白1（PD-1）在根除AML方面的协同作用。总的来说，研究结果显示，PRMT9在LSCs和非LSCs的存活和免疫逃逸中发挥作用，靶向PRMT9可能成为一种潜在的抗癌策略。

5.A randomized, non-comparative phase 2 study of neoadjuvant immune-checkpoint blockade in retroperitoneal dedifferentiated liposarcoma and extremity/truncal undifferentiated pleomorphic sarcoma

一项关于腹膜后去分化脂肪肉瘤和四肢/躯干未分化多形性肉瘤新辅助免疫检查点阻断的随机、非比较性2期研究

Abstract

Based on the demonstrated clinical activity of immune-checkpoint blockade (ICB) in advanced dedifferentiated liposarcoma (DDLPS) and undifferentiated pleomorphic sarcoma (UPS), we conducted a randomized, non-comparative phase 2 trial (NCT03307616) of neoadjuvant nivolumab or nivolumab/ipilimumab in patients with resectable retroperitoneal DDLPS (n = 17) and extremity/truncal UPS (+ concurrent nivolumab/radiation therapy; n = 10). The primary end point of pathologic response (percent hyalinization) was a median of 8.8% in DDLPS and 89% in UPS. Secondary end points were the changes in immune infiltrate, radiographic response, 12- and 24-month relapse-free survival and overall survival. Lower densities of regulatory T cells before treatment were associated with a major pathologic response (hyalinization > 30%). Tumor infiltration by B cells was increased following neoadjuvant treatment and was associated with overall survival in DDLPS. B cell infiltration was associated with higher densities of regulatory T cells before treatment, which was lost upon ICB treatment. Our data demonstrate that neoadjuvant ICB is associated with complex immune changes within the tumor microenvironment in DDLPS and UPS and that neoadjuvant ICB with concurrent radiotherapy has significant efficacy in UPS.

摘要

基于免疫检查点阻断剂（ICB）在晚期去分化脂肪肉瘤（DDLPS）和未分化多形性肉瘤（UPS）中已证实的临床活性，该研究开展了一项随机、非对照的2期临床试验（NCT03307616），评估新辅助治疗纳武利尤单抗或纳武利尤单抗联合伊匹木单抗在可切除的腹膜后DDLPS（n = 17）和四肢/躯干UPS（联合尼伏单抗和放射治疗；n = 10）患者中的疗效。主要结局是病理反应（玻璃样变的百分比），结果显示DDLPS中位数为8.8%，而UPS为89%。次要结局包括免疫浸润的变化、影像学反应、12个月和24个月无复发生存率和总生存率。研究发现，治疗前调节性T细胞密度较低与主要病理反应（玻璃样变性>30%）相关。新辅助治疗后B细胞的肿瘤浸润增加，并与DDLPS中的总生存率相关。B细胞浸润与治疗前调节性T细胞密度较高相关，但这种关联在ICB治疗后消失。总之，该研究的数据表明，新辅助ICB治疗与DDLPS和UPS肿瘤微环境中复杂的免疫变化相关，并且新辅助ICB联合放射治疗在UPS中具有显著的疗效。

6.Sarcoma microenvironment cell states and ecosystems are associated with prognosis and predict response to immunotherapy

肉瘤微环境中的细胞状态和生态系统与预后相关，并可预测对免疫疗法的反应

Abstract

Characterization of the diverse malignant and stromal cell states that make up soft tissue sarcomas and their correlation with patient outcomes has proven difficult using fixed clinical specimens. Here, we employed EcoTyper, a machine-learning framework, to identify the fundamental cell states and cellular ecosystems that make up sarcomas on a large scale using bulk transcriptomes with clinical annotations. We identified and validated 23 sarcoma-specific, transcriptionally defined cell states, many of which were highly prognostic of patient outcomes across independent datasets. We discovered three conserved cellular communities or ecotypes associated with underlying genomic alterations and distinct clinical outcomes. We show that one ecotype defined by tumor-associated macrophages and epithelial-like malignant cells predicts response to immune-checkpoint inhibition but not chemotherapy and validate our findings in an independent cohort. Our results may enable identification of patients with soft tissue sarcomas who could benefit from immunotherapy and help develop new therapeutic strategies.

摘要

软组织肉瘤的复杂性在于其内部恶性细胞和基质细胞状态的多样性，这些状态与患者预后之间的关联很难通过传统的固定临床样本来确定。本研究中，研究者使用了EcoTyper这一机器学习框架，对大量具有临床注释的转录组数据进行分析，识别出了构成肉瘤的基本细胞状态和细胞生态系统。研究成功鉴定并验证了23种与肉瘤特异性的、在转录层面具有明确定义的细胞状态，其中许多细胞状态在多个独立数据集中都对患者预后有显著的预测价值。研究还发现了三类与基因组变异和不同临床结局紧密相关的保守细胞群落，即生态类型。特别值得一提的是，其中一种生态类型由肿瘤相关巨噬细胞和类上皮恶性细胞组成，能够预测患者对免疫检查点抑制剂的反应，但对化疗药物则没有这种预测能力。随后，研究在另一个独立队列中对这一发现进行了验证。以上结果有助于识别出可能从免疫治疗中获益的软组织肉瘤患者，并为开发新的治疗方法提供指导。

7.Mitochondrial DNA mutations drive aerobic glycolysis to enhance checkpoint blockade response in melanoma

线粒体DNA突变驱动有氧糖酵解，以增强黑色素瘤对免疫检查点的阻断反应

Abstract

The mitochondrial genome (mtDNA) encodes essential machinery for oxidative phosphorylation and metabolic homeostasis. Tumor mtDNA is among the most somatically mutated regions of the cancer genome, but whether these mutations impact tumor biology is debated. We engineered truncating mutations of the mtDNA-encoded complex I gene, Mt-Nd5, into several murine models of melanoma. These mutations promoted a Warburg-like metabolic shift that reshaped tumor microenvironments in both mice and humans, consistently eliciting an anti-tumor immune response characterized by loss of resident neutrophils. Tumors bearing mtDNA mutations were sensitized to checkpoint blockade in a neutrophil-dependent manner, with induction of redox imbalance being sufficient to induce this effect in mtDNA wild-type tumors. Patient lesions bearing >50% mtDNA mutation heteroplasmy demonstrated a response rate to checkpoint blockade that was improved by ~2.5-fold over mtDNA wild-type cancer. These data nominate mtDNA mutations as functional regulators of cancer metabolism and tumor biology, with potential for therapeutic exploitation and treatment stratification.

摘要

线粒体基因组（mtDNA）编码氧化磷酸化和维持代谢稳态所需的关键组分。尽管肿瘤中的mtDNA是基因组中突变频率最多的部分，但这些突变对肿瘤特性的具体影响仍有待明确。该研究通过基因工程技术，在多种小鼠黑色素瘤模型中引入了线粒体复合体I的编码基因Mt-Nd5的截断突变。这些突变触发了一种类似于Warburg效应的代谢转变，可以重塑小鼠和人类的肿瘤微环境，并都能引发一种以局部中性粒细胞减少为特征的抗肿瘤免疫反应。携带这些mtDNA突变的肿瘤对免疫检查点阻断治疗的敏感性增强，这种敏感性依赖于中性粒细胞，而在mtDNA野生型肿瘤中，可以通过诱导氧化还原失衡产生相同的效果。携带超过50% mtDNA突变异质性的患者样本，对免疫检查点阻断治疗的响应率比mtDNA野生型肿瘤高了大约2.5倍。这些结果表明，mtDNA突变是癌症代谢和肿瘤生物学的功能性调控因素，为治疗策略的开发和治疗分层提供了新的可能性。

2024年5月，第5卷第5期共发表13篇文章，其中1篇Turning Points；2篇News & Views；1篇Research Briefings；1篇Review Articles；6篇Research；2篇Amendments & Corrections。

1.Efferocytosis reprograms the tumor microenvironment to promote pancreatic cancer liver metastasis（封面文章）

胞葬作用重编程肿瘤微环境以促进胰腺癌的肝脏转移

Abstract

Pancreatic ductal adenocarcinoma is a highly metastatic disease and macrophages support liver metastases. Efferocytosis, or engulfment of apoptotic cells by macrophages, is an essential process in tissue homeostasis and wound healing, but its role in metastasis is less well understood. Here, we found that the colonization of the hepatic metastatic site is accompanied by low-grade tissue injury and that efferocytosis-mediated clearance of parenchymal dead cells promotes macrophage reprogramming and liver metastasis. Mechanistically, progranulin expression in macrophages is necessary for efficient efferocytosis by controlling lysosomal acidification via cystic fibrosis transmembrane conductance regulator and the degradation of lysosomal cargo, resulting in LXRα/RXRα-mediated macrophage conversion and upregulation of arginase 1. Pharmacological blockade of efferocytosis or macrophage-specific genetic depletion of progranulin impairs macrophage conversion, improves CD8+ T cell functions, and reduces liver metastasis. Our findings reveal how hard-wired functions of macrophages in tissue repair contribute to liver metastasis and identify potential targets for prevention of pancreatic ductal adenocarcinoma liver metastasis.

摘要

胰腺导管腺癌是一种高度转移性疾病，巨噬细胞支持其发生肝转移。胞葬作用，即巨噬细胞吞噬凋亡细胞的过程，对于组织稳态的维持和伤口愈合是必不可少的，但其在肿瘤转移中的作用尚不清楚。在这里，该研究发现肝脏转移部位的定植常伴随着低度的组织损伤，而且胞葬作用介导的实质死亡细胞的清除促进了巨噬细胞的重编程和肝转移。从机制上讲，巨噬细胞中的颗粒蛋白前体（progranulin）表达对于凋亡细胞的有效清除至关重要，它通过控制囊性纤维化跨膜传导调节因子和溶酶体货物的降解来调节溶酶体酸化，从而实现LXRα/RXRα介导的巨噬细胞转化和精氨酸酶1的上调。用药物阻断胞葬作用或巨噬细胞特异性基因敲除颗粒蛋白前体（progranulin）会抑制巨噬细胞的转化，改善CD8+ T细胞的功能，并减少肝脏转移。该研究的发现揭示了巨噬细胞在组织修复中的固有功能如何促进肝转移，并确定了预防胰腺导管腺癌肝转移的潜在靶点。

2.Lung endothelium exploits susceptible tumor cell states to instruct metastatic latency

肺内皮细胞利用肿瘤细胞的易感状态来指导转移性潜伏期

Abstract

In metastasis, cancer cells travel around the circulation to colonize distant sites. Due to the rarity of these events, the immediate fates of metastasizing tumor cells (mTCs) are poorly understood while the role of the endothelium as a dissemination interface remains elusive. Using a newly developed combinatorial mTC enrichment approach, we provide a transcriptional blueprint of the early colonization process. Following their arrest at the metastatic site, mTCs were found to either proliferate intravascularly or extravasate, thereby establishing metastatic latency. Endothelial-derived angiocrine Wnt factors drive this bifurcation, instructing mTCs to follow the extravasation–latency route. Surprisingly, mTC responsiveness towards niche-derived Wnt was established at the epigenetic level, which predetermined tumor cell behavior. Whereas hypomethylation enabled high Wnt activity leading to metastatic latency, methylated mTCs exhibited low activity and proliferated intravascularly. Collectively the data identify the predetermined methylation status of disseminated tumor cells as a key regulator of mTC behavior in the metastatic niche.

摘要

在癌症转移过程中，癌细胞在循环系统中游走，寻找远处的定植点。由于这些事件的罕见性，我们对转移性肿瘤细胞（mTCs）的即时命运仍缺乏了解，内皮细胞在癌细胞扩散中的作用也尚未明确。因此，通过一种新近开发的综合mTC富集技术，该研究绘制了肿瘤早期定植过程的基因转录图谱。mTCs在到达转移部位后，要么在血管内增殖，要么渗出血管壁，建立转移的潜伏状态。内皮细胞释放的血管生长因子Wnt家族，引导了这一分化过程，促使mTCs渗出血管壁和建立潜伏状态。令人意外的是，mTCs对微环境中Wnt信号的反应性 在表观遗传层面上就已经确定，这预先决定了肿瘤细胞的行为模式。低甲基化状态使mTCs能够高度响应Wnt信号，从而进入潜伏期；而甲基化的mTCs则因Wnt信号活性低而在血管内增殖。这些数据表明，mTCs的甲基化状态是调控它们在转移微环境中行为的关键因素。

3.Associations of seven measures of biological age acceleration with frailty and all-cause mortality among adult survivors of childhood cancer in the St. Jude Lifetime Cohort

在圣裘德终生队列中，七种生物年龄加速指标与儿童癌症成年幸存者的虚弱状态和全因死亡率之间的关系

Abstract

Survivors of childhood cancer may experience accelerated biological aging, resulting in premature frailty and death. We used seven measures of biological age in the St. Jude Lifetime (SJLIFE) Cohort to compare biological age acceleration between the SJLIFE Cohort and the third United States National Health and Nutrition Examination Survey controls, explore trajectories of biological age according to cancer treatment and type, and test associations of biological age acceleration with frailty and death (mean follow-up of 26.5 years) among survivors. Survivors of cancer aged 5% faster per year and measured, on average, 0.6–6.44 years biologically older compared to controls and 5–16 years biologically older compared to age-matched individuals at the population level. Survivors treated with hematopoietic cell transplant and vinca alkaloid chemotherapy evidenced the fastest trajectories of biological aging. Biologically, older and faster-aging survivors consistently and robustly had a higher risk of frailty and died earlier than those with slower biological aging, suggesting a potential opportunity to intervene on excess aging.

摘要

儿童癌症幸存者可能会经历加速的生物学衰老，导致过早的虚弱和死亡。该研究使用了圣裘德终生队列（SJLIFE）中的七种生物年龄测量方法，比较了SJLIFE队列与第三次美国国家健康和营养检查调查对照组之间的生物年龄加速情况，根据癌症治疗和类型探索生物年龄的轨迹，并测试了幸存者中生物年龄加速与虚弱和死亡之间的关联（平均随访26.5年）。研究发现，癌症幸存者的生物年龄每年加速增长5%，比对照组平均生物年龄大0.6-6.44岁，与年龄匹配的人群相比生物年龄大了5-16岁。其中，接受造血细胞移植和长春花生物碱化疗治疗的幸存者生物学衰老轨迹最快。在生物学上，年龄较大和快速衰老的幸存者的虚弱风险明显高于衰老较慢的幸存者，并且死亡时间也更早，这表明需要干预过度老化的情况。

4.Modeling T cell temporal response to cancer immunotherapy rationalizes development of combinatorial treatment protocols

对T细胞对癌症免疫疗法的时间反应进行建模，使联合治疗方案的开发合理化

Abstract

Successful immunotherapy relies on triggering complex responses involving T cell dynamics in tumors and the periphery. Characterizing these responses remains challenging using static human single-cell atlases or mouse models. To address this, we developed a framework for in vivo tracking of tumor-specific CD8+ T cells over time and at single-cell resolution. Our tools facilitate the modeling of gene program dynamics in the tumor microenvironment (TME) and the tumor-draining lymph node (tdLN). Using this approach, we characterize two modes of anti-programmed cell death protein 1 (PD-1) activity, decoupling induced differentiation of tumor-specific activated precursor cells from conventional type 1 dendritic cell (cDC1)-dependent proliferation and recruitment to the TME. We demonstrate that combining anti-PD-1 therapy with anti-4-1BB agonist enhances the recruitment and proliferation of activated precursors, resulting in tumor control. These data suggest that effective response to anti-PD-1 therapy is dependent on sufficient influx of activated precursor CD8+ cells to the TME and highlight the importance of understanding system-level dynamics in optimizing immunotherapies.

摘要

成功的免疫疗法依赖于触发涉及肿瘤和周边T细胞动力学的复杂反应。然而，我们很难通过静态的人类单细胞图谱或小鼠模型来描述这些反应。为了解决这个问题，该研究开发了一个框架，用于在体内实时追踪肿瘤特异性的CD8+ T细胞，并能在单细胞分辨率下进行观察。这个工具有助于模拟肿瘤微环境（TME）和肿瘤引流淋巴结（tdLN）中的基因程序动态。通过这种方法，研究者阐述了抗程序性细胞死亡蛋白1（PD-1）的两种作用模式，将肿瘤特异性激活前体细胞的诱导分化与依赖于传统的1型树突状细胞（cDC1）的增殖和肿瘤微环境（TME）中的招募过程区分开来。另外，研究证明，将抗PD-1疗法与抗4-1BB激动剂联合使用，可以增强激活前体细胞的招募和增殖，从而实现对肿瘤的控制。这些数据表明，抗PD-1疗法的有效反应依赖于足够数量的激活前体CD8+T细胞流入TME，并强调了在优化免疫疗法时理解系统级动态的重要性。

5.Synthetic dual co-stimulation increases the potency of HIT and TCR-targeted cell therapies

合成的双重共刺激增强了HIT和TCR靶向细胞疗法的效力

Abstract

Chimeric antigen receptor T cells have dramatically improved the treatment of hematologic malignancies. T cell antigen receptor (TCR)-based cell therapies are yet to achieve comparable outcomes. Importantly, chimeric antigen receptors not only target selected antigens but also reprogram T cell functions through the co-stimulatory pathways that they engage upon antigen recognition. We show here that a fusion receptor comprising the CD80 ectodomain and the 4-1BB cytoplasmic domain, termed 80BB, acts as both a ligand and a receptor to engage the CD28 and 4-1BB pathways, thereby increasing the antitumor potency of human leukocyte antigen-independent TCR (HIT) receptor- or TCR-engineered T cells and tumor-infiltrating lymphocytes. Furthermore, 80BB serves as a switch receptor that provides agonistic 4-1BB co-stimulation upon its ligation by the inhibitory CTLA4 molecule. By combining multiple co-stimulatory features in a single antigen-agnostic synthetic receptor, 80BB is a promising tool to sustain CD3-dependent T cell responses in a wide range of targeted immunotherapies.

摘要

嵌合抗原受体T细胞显著改善了血液恶性肿瘤的治疗效果。但基于T细胞抗原受体（TCR）的细胞疗法尚未达到类似的疗效。重要的是，嵌合抗原受体不仅能靶向选定的抗原，还能在抗原识别时激活共刺激途径重新编程T细胞功能。该研究在这里展示了一种融合受体，由CD80的细胞外区域和4-1BB的细胞质区域组成，称为80BB，它既作为配体又作为受体来激活CD28和4-1BB途径，从而增强了人类白细胞抗原非依赖性TCR（HIT）受体或TCR工程化T细胞以及肿瘤浸润性淋巴细胞的抗肿瘤效力。此外，80BB作为一种转化受体，当其被抑制性CTLA4分子结合时，可以提供激动性的4-1BB共刺激。总之，通过将多个共刺激特征结合在单个抗原非特异性合成受体中，80BB成为一个有前景的工具，可以在广泛的靶向免疫疗法中维持CD3依赖的T细胞反应。

6.Intra-tumoral T cells in pediatric brain tumors display clonal expansion and effector properties

儿童脑肿瘤中的肿瘤内T细胞表现出克隆扩增和效应特性

Abstract

Brain tumors in children are a devastating disease in a high proportion of patients. Owing to inconsistent results in clinical trials in unstratified patients, the role of immunotherapy remains unclear. We performed an in-depth survey of the single-cell transcriptomes and clonal relationship of intra-tumoral T cells from children with brain tumors. Our results demonstrate that a large fraction of T cells in the tumor tissue are clonally expanded with the potential to recognize tumor antigens. Such clonally expanded T cells display enrichment of transcripts linked to effector function, tissue residency, immune checkpoints and signatures of neoantigen-specific T cells and immunotherapy response. We identify neoantigens in pediatric brain tumors and show that neoantigen-specific T cell gene signatures are linked to better survival outcomes. Notably, among the patients in our cohort, we observe substantial heterogeneity in the degree of clonal expansion and magnitude of T cell response. Our findings suggest that characterization of intra-tumoral T cell responses may enable selection of patients for immunotherapy, an approach that requires prospective validation in clinical trials.

摘要

儿童脑肿瘤在很大一部分病人中是一种毁灭性的疾病。由于未分层患者的临床试验结果不一致，免疫疗法的作用仍然不明确。该研究对患有脑肿瘤的儿童的肿瘤内T细胞的单细胞转录组和克隆关系进行了深入研究。结果显示，肿瘤组织中有很大一部分T细胞发生了克隆扩增，具有识别肿瘤抗原的潜力。这些克隆扩增的T细胞表现出与效应功能、组织驻留、免疫检查点以及新抗原特异性T细胞和免疫疗法反应相关的转录本的富集。研究鉴定了儿童脑肿瘤中的新抗原，并表明新抗原特异性T细胞基因特征与更好的生存结局相关联。值得注意的是，在该研究的队列中，研究者观察到克隆扩增程度和T细胞反应的强度存在显著的异质性。总之，研究结果表明，对肿瘤内T细胞反应的表征可能有助于选择适合免疫疗法的患者，但这种方法需要在临床试验中进行前瞻性验证。

汇报人：吴婷婷

导师：任建君

审核：夏晓旭、李朔、任建君