【Cancer Cell】2024年5-6月刊论文导读
期刊介绍：
Cancer Cell创刊于2002年，由CELL PRESS出版商出版，收稿方向涵盖医学-肿瘤学全领域，在行业领域中学术影响力很大，属于TOP期刊，国际一流期刊。审议手稿的主要标准是研究是否在回答与自然发生的癌症有关的重要问题方面取得重大进展。影响因子指数48.8。2024年5-6月一共发表40篇，包括Commentaries 5篇，Previews 8篇，Article 17篇，Corrections 3篇，Letters 1篇，Report 1篇，Spotlight 1篇，Perspective 1篇，Voices 1篇，Review 1篇，Editorial note 1篇。
May 13，2024 Volume 42，Issue 5，p723-914
2024年5月，Cancer Cell共发表17篇文章，其中包括Commentaries 2篇，Letter 1篇，Previews 4篇，Perspective 1篇，Articles 8篇，Report 1篇。
1.Comprehensive peripheral blood immunoprofiling reveals five immunotypes with immunotherapy response characteristics in patients with cancer
全面的外周血免疫表型分析揭示了癌症患者中具有免疫治疗反应特征的五种免疫表型类型
美国BostonGene公司；美国托马斯·杰斐逊大学
Summary
The lack of comprehensive diagnostics and consensus analytical models for evaluating the status of a patient’s immune system has hindered a wider adoption of immunoprofiling for treatment monitoring and response prediction in cancer patients. To address this unmet need, we developed an immunoprofiling platform that uses multiparameter flow cytometry to characterize immune cell heterogeneity in the peripheral blood of healthy donors and patients with advanced cancers. Using unsupervised clustering, we identified five immunotypes with unique distributions of different cell types and gene expression profiles. An independent analysis of 17,800 open-source transcriptomes with the same approach corroborated these findings. Continuous immunotype-based signature scores were developed to correlate systemic immunity with patient responses to different cancer treatments, including immunotherapy, prognostically and predictively. Our approach and findings illustrate the potential utility of a simple blood test as a flexible tool for stratifying cancer patients into therapy response groups based on systemic immunoprofiling.
摘要：
缺乏全面的诊断和一致的分析模型来评估患者的免疫系统状态阻碍了在癌症患者中更广泛地采用免疫谱来进行治疗监测和反应预测。为了解决这一未满足的需求，研究者开发了一个免疫谱平台，该平台使用多参数流式细胞术来表征健康供体和晚期癌症患者外周血中的免疫细胞异质性。使用无监督聚类，研究者确定了五种免疫表型，它们具有不同细胞类型和基因表达谱的独特分布。用同样的方法对17，800个开源转录组的独立分析进一步证实了这些发现。基于上述发现，该研究进一步开发了基于免疫分型的特征评分，以将全身免疫细胞表型与患者对不同癌症治疗（包括免疫疗法）的反应相关联，进行预测。总之，本研究证明了一个简单的血液测试可作为基于免疫谱将癌症患者分成治疗反应组的灵活工具。
2.Clinical drug screening reveals clofazimine potentiates the efficacy while reducing the toxicity of anti-PD-1 and CTLA-4 immunotherapy
临床药物筛选实验发现氯法齐明可增强抗PD-1和CTLA-4免疫治疗的疗效，同时降低其毒性
美国威克森林浸会癌症中心
Summary
Emerging as the most potent and durable combinational immunotherapy, dual anti-PD-1 and CTLA-4 immune checkpoint blockade (ICB) therapy notoriously increases grade 3–5 immune-related adverse events (irAEs) in patients. Accordingly, attempts to improve the antitumor potency of anti-PD-1+CTLA-4 ICB by including additional therapeutics have been largely discouraged due to concerns of further increasing fatal toxicity. Here, we screened ∼3,000 Food and Drug Administration (FDA)-approved drugs and identified clofazimine as a potential third agent to optimize anti-PD-1+CTLA-4 ICB. Remarkably, clofazimine outperforms ICB dose reduction or steroid treatment in reversing lethality of irAEs, but unlike the detrimental effect of steroids on antitumor efficacy, clofazimine potentiates curative responses in anti-PD-1+CTLA-4 ICB. Mechanistically, clofazimine promotes E2F1 activation in CD8+ T cells to overcome resistance and counteracts pathogenic Th17 cells to abolish irAEs. Collectively, clofazimine potentiates the antitumor efficacy of anti-PD-1+CTLA-4 ICB, curbs intractable irAEs, and may fill a desperate clinical need to improve patient survival.
摘要：
作为最有效和最持久的联合免疫疗法，双重抗PD-1和CTLA-4免疫检查点阻断（ICB）疗法增加了患者出现3-5级免疫相关不良事件（irAEs）的风险。因此，为防止进一步增加的致命毒性，一般不再增加额外的治疗剂来提高抗PD-1+CTLA-4 ICB的抗肿瘤效力。本研究筛选了3000种美国食品药品监督管理局（FDA）批准的药物，并确定氯法齐明是优化抗PD-1+CTLA-4 ICB的潜在第三种药物。值得注意的是，在逆转irAEs致死率方面，氯法齐明优于将ICB剂量减少或使用类固醇治疗等方案，同时与类固醇对抗肿瘤疗效的有害作用不同，氯法齐明在抗PD-1+CTLA-4 ICB中增强了治疗反应。从机理上讲，氯法齐明促进了CD8+ T细胞中E2F1的激活以克服耐药性，并对抗致病性Th17细胞以消除irAEs。总的来说，氯法齐明增强了抗PD-1+CTLA-4 ICB的抗肿瘤功效，抑制了难治性irAEs，并可能满足改善患者存活率的迫切临床需求。
3.Tracking in situ checkpoint inhibitor-bound target T cells in patients with checkpoint-induced colitis
在检查点抑制剂诱导的结肠炎患者中追踪原位检查点抑制剂结合的靶T细胞
英国牛津大学约翰·拉德克利夫医院
Summary
The success of checkpoint inhibitors (CPIs) for cancer has been tempered by immune-related adverse effects including colitis. CPI-induced colitis is hallmarked by expansion of resident mucosal IFNγ cytotoxic CD8+ T cells, but how these arise is unclear. Here, we track CPI-bound T cells in intestinal tissue using multimodal single-cell and subcellular spatial transcriptomics (ST). Target occupancy was increased in inflamed tissue, with drug-bound T cells located in distinct microdomains distinguished by specific intercellular signaling and transcriptional gradients. CPI-bound cells were largely CD4+ T cells, including enrichment in CPI-bound peripheral helper, follicular helper, and regulatory T cells. IFNγ CD8+ T cells emerged from both tissue-resident memory (TRM) and peripheral populations, displayed more restricted target occupancy profiles, and co-localized with damaged epithelial microdomains lacking effective regulatory cues. Our multimodal analysis identifies causal pathways and constitutes a resource to inform novel preventive strategies.
摘要：
检查点抑制剂（CPI）治疗癌症的成功受到了包括结肠炎在内的免疫相关副作用的影响。CPI诱导的结肠炎的特征是常驻粘膜IFNγ细胞毒性CD8+ T细胞的扩增，但具体机制尚不清楚。本文使用多模式单细胞和亚细胞空间转录组学（ST）追踪肠组织中CPI结合的T细胞。炎症组织中的靶细胞占用率增加，结合CPI的T细胞位于由特定细胞间信号和转录梯度定义的特定微域中。CPI结合的细胞主要是CD4+ T细胞，包括富含CPI结合的外周辅助细胞、滤泡辅助细胞和调节性T细胞。IFNγ CD8+ T细胞起源于组织驻留记忆（TRM）和外周细胞群，其靶点占有率更为受限，并与缺乏有效调节信号的受损上皮微区共定位。本研究的多模态分析确定了因果路径，并提供一种新的预防策略。
4.Identification of hypoxic macrophages in glioblastoma with therapeutic potential for vasculature normalization
鉴定胶质母细胞瘤中具有血管正常化治疗潜力的缺氧巨噬细胞
陆军军医大学第一附属医院临床病理研究所
Summary
Monocyte-derived tumor-associated macrophages (Mo-TAMs) intensively infiltrate diffuse gliomas with remarkable heterogeneity. Using single-cell transcriptomics, we chart a spatially resolved transcriptional landscape of Mo-TAMs across 51 patients with isocitrate dehydrogenase (IDH)-wild-type glioblastomas or IDH-mutant gliomas. We characterize a Mo-TAM subset that is localized to the peri-necrotic niche and skewed by hypoxic niche cues to acquire a hypoxia response signature. Hypoxia-TAM destabilizes endothelial adherens junctions by activating adrenomedullin paracrine signaling, thereby stimulating a hyperpermeable neovasculature that hampers drug delivery in glioblastoma xenografts. Accordingly, genetic ablation or pharmacological blockade of adrenomedullin produced by Hypoxia-TAM restores vascular integrity, improves intratumoral concentration of the anti-tumor agent dabrafenib, and achieves combinatorial therapeutic benefits. Increased proportion of Hypoxia-TAM or adrenomedullin expression is predictive of tumor vessel hyperpermeability and a worse prognosis of glioblastoma. Our findings highlight Mo-TAM diversity and spatial niche-steered Mo-TAM reprogramming in diffuse gliomas and indicate potential therapeutics targeting Hypoxia-TAM to normalize tumor vasculature.
摘要：
单核细胞来源的肿瘤相关巨噬细胞（Mo-TAMs）是胶质母细胞瘤中主要的免疫浸润细胞，具有显著的异质性。利用单细胞转录组学，研究者绘制了51例异柠檬酸脱氢酶（IDH）-野生型胶质母细胞瘤或IDH突变型胶质细胞瘤患者的Mo-TAMs的空间分辨转录图谱。研究者鉴定出一个位于坏死灶周围微环境的Mo-TAM亚群，该亚群受缺氧微环境信号的调控，从而获得缺氧反应特征。缺氧-TAM通过激活肾上腺髓质素旁分泌信号使内皮粘附连接不稳定，从而刺激形成高渗透性新血管系统，阻碍胶质母细胞瘤异种移植模型中的药物递送。因此，对缺氧-TAM产生的肾上腺髓质素进行基因敲除或药物阻断可恢复血管的完整性，提高抗肿瘤药物达拉非尼的肿瘤内浓度，并获得联合治疗的益处。缺氧TAM或肾上腺髓质素表达比例增加预示着肿瘤血管通透性增高和胶质母细胞瘤预后不良。该研究的发现强调了弥漫性胶质瘤中Mo-TAM的多样性和空间微环境引导的Mo-TAM重编程，并指出了以缺氧巨噬细胞为靶点的潜在治疗方法，以实现肿瘤血管的正常化。。
5.Molecular targets of glucocorticoids that elucidate their therapeutic efficacy in aggressive lymphomas
糖皮质激素在治疗侵袭性淋巴瘤中的分子靶点
美国国立卫生研究院国家癌症研究所
Summary
Glucocorticoids have been used for decades to treat lymphomas without an established mechanism of action. Using functional genomic, proteomic, and chemical screens, we discover that glucocorticoids inhibit oncogenic signaling by the B cell receptor (BCR), a recurrent feature of aggressive B cell malignancies, including diffuse large B cell lymphoma and Burkitt lymphoma. Glucocorticoids induce the glucocorticoid receptor (GR) to directly transactivate genes encoding negative regulators of BCR stability (LAPTM5; KLHL14) and the PI3 kinase pathway (INPP5D; DDIT4). GR directly represses transcription of CSK, a kinase that limits the activity of BCR-proximal Src-family kinases. CSK inhibition attenuates the constitutive BCR signaling of lymphomas by hyperactivating Src-family kinases, triggering their ubiquitination and degradation. With the knowledge that glucocorticoids disable oncogenic BCR signaling, they can now be deployed rationally to treat BCR-dependent aggressive lymphomas and used to construct mechanistically sound combination regimens with inhibitors of BTK, PI3 kinase, BCL2, and CSK.
摘要：
糖皮质激素已经用于治疗淋巴瘤长达几十年，但其作用机制尚不清楚。本文使用功能基因组学、蛋白质组学和化学筛选，发现糖皮质激素抑制B细胞受体（BCR）的致癌信号，这是包括弥漫性大B细胞淋巴瘤和伯基特淋巴瘤在内的侵袭性B细胞恶性肿瘤的共同特征。糖皮质激素诱导糖皮质激素受体（GR）直接反式激活编码BCR稳定性负性调节因子（LAPTM5；KLHL14）和PI3激酶途径负调节因子（INPP5D；DDIT4）。GR还直接抑制CSK（一种限制BCR近端Src家族激酶活性的激酶）的转录。CSK抑制通过过度激活Src家族激酶，触发其泛素化和降解来减弱淋巴瘤的组成型BCR信号。随着对糖皮质激素抑制致癌BCR信号的了解，现在可以合理地使用糖皮质激素治疗BCR依赖性侵袭性淋巴瘤，并用于构建与BTK、PI3激酶、BCL2和CSK抑制剂的机制合理的联合治疗方案。
6、Putting the STING back into BH3-mimetic drugs for TP53-mutant blood cancers
STING协同BH3模拟药物用于TP53突变血液系统恶性肿瘤的治疗
澳大利亚沃尔特和伊丽莎霍尔医学研究所
Summary
TP53-mutant blood cancers remain a clinical challenge. BH3-mimetic drugs inhibit BCL-2 pro-survival proteins, inducing cancer cell apoptosis. Despite acting downstream of p53, functional p53 is required for maximal cancer cell killing by BH3-mimetics through an unknown mechanism. Here, we report p53 is activated following BH3-mimetic induced mitochondrial outer membrane permeabilization, leading to BH3-only protein induction and thereby potentiating the pro-apoptotic signal. TP53-deficient lymphomas lack this feedforward loop, providing opportunities for survival and disease relapse after BH3-mimetic treatment. The therapeutic barrier imposed by defects in TP53 can be overcome by direct activation of the cGAS/STING pathway, which promotes apoptosis of blood cancer cells through p53-independent BH3-only protein upregulation. Combining clinically relevant STING agonists with BH3-mimetic drugs efficiently kills TRP53/TP53-mutant mouse B lymphoma, human NK/T lymphoma, and acute myeloid leukemia cells. This represents a promising therapy regime that can be fast-tracked to tackle TP53-mutant blood cancers in the clinic.
摘要：
携带TP53突变的血液系统恶性肿瘤仍然是临床治疗难题。BH3模拟药物能够抑制BCL-2促存活蛋白，诱导癌细胞凋亡。尽管该药物作用于p53的下游，但功能性p53是BH3模拟物实现最大癌细胞杀伤程度却是必需的，尽管其具体机制尚不清楚。本文报道了p53在BH3模拟物诱导的线粒体外膜通透化后被激活，进而诱导仅含BH3结构域的蛋白表达，从而加强促凋亡信号。TP53缺陷型淋巴瘤缺乏这种正反馈，为BH3模拟治疗后的生存和疾病复发提供了机会。TP53缺陷造成的治疗障碍可以通过直接激活cGAS/STING途径来克服，该通路通过上调不依赖于p53的仅含BH3结构域的蛋白，促进血癌细胞凋亡。将临床相关的STING激动剂与BH3模拟药物结合，可有效杀死TRP53/TP53突变小鼠B淋巴瘤、人类NK/T淋巴瘤和急性髓细胞白血病细胞。这提供了一种有希望的治疗方案，可以在临床上快速解决TP53突变型血液系统恶性肿瘤。
7.Tumor cell-intrinsic epigenetic dysregulation shapes cancer-associated fibroblasts heterogeneity to metabolically support pancreatic cancer
肿瘤细胞固有的表观遗传失调调控了胰腺癌相关成纤维细胞异质性及代谢重塑
上海交通大学医学院附属仁济医院
Summary
The tumor microenvironment (TME) in pancreatic ductal adenocarcinoma (PDAC) involves a significant accumulation of cancer-associated fibroblasts (CAFs) as part of the host response to tumor cells. The origins and functions of transcriptionally diverse CAF populations in PDAC remain poorly understood. Tumor cell-intrinsic genetic mutations and epigenetic dysregulation may reshape the TME; however, their impacts on CAF heterogeneity remain elusive. SETD2, a histone H3K36 trimethyl-transferase, functions as a tumor suppressor. Through single-cell RNA sequencing, we identify a lipid-laden CAF subpopulation marked by ABCA8a in Setd2-deficient pancreatic tumors. Our findings reveal that tumor-intrinsic SETD2 loss unleashes BMP2 signaling via ectopic gain of H3K27Ac, leading to CAFs differentiation toward lipid-rich phenotype. Lipid-laden CAFs then enhance tumor progression by providing lipids for mitochondrial oxidative phosphorylation via ABCA8a transporter. Together, our study links CAF heterogeneity to epigenetic dysregulation in tumor cells, highlighting a previously unappreciated metabolic interaction between CAFs and pancreatic tumor cells.
摘要：
胰腺导管腺癌（PDAC）中的肿瘤微环境（TME）包含大量肿瘤相关成纤维细胞（CAFs）的积聚，这是宿主对肿瘤细胞反应的一部分。PDAC中转录多样性CAF群体的起源和功能仍然不清楚。肿瘤细胞内在基因突变和表观遗传失调可能重塑肿瘤微环境，然而，它们对CAF异质性的影响仍不清楚。SETD2是一种组蛋白H3K36三甲基转移酶，具有肿瘤抑制作用。通过单细胞RNA测序，研究者在Setd2缺陷型胰腺肿瘤中发现了一个由ABCA8a标记的高脂CAF亚群。该发现揭示了肿瘤内在SETD2缺失通过H3K27Ac的异位获得释放BMP2信号，导致CAFs向富含脂质的表型分化。然后，高脂CAFs通过ABCA8a转运蛋白为线粒体氧化磷酸化提供脂质，从而促进肿瘤进展。总之，该研究将CAF异质性与肿瘤细胞表观遗传失调联系起来，强调了CAF和胰腺肿瘤细胞之间以前未被重视的代谢相互作用。
8.The crosstalk between macrophages and cancer cells potentiates pancreatic cancer cachexia
巨噬细胞和癌细胞之间的相互作用加重了胰腺癌恶病质
美国荷马大学健康科学中心医学系
Summary
With limited treatment options, cachexia remains a major challenge for patients with cancer. Characterizing the interplay between tumor cells and the immune microenvironment may help identify potential therapeutic targets for cancer cachexia. Herein, we investigate the critical role of macrophages in potentiating pancreatic cancer induced muscle wasting via promoting TWEAK (TNF-like weak inducer of apoptosis) secretion from the tumor. Specifically, depletion of macrophages reverses muscle degradation induced by tumor cells. Macrophages induce non-autonomous secretion of TWEAK through CCL5/TRAF6/NF-κB pathway. TWEAK promotes muscle atrophy by activating MuRF1 initiated muscle remodeling. Notably, tumor cells recruit and reprogram macrophages via the CCL2/CCR2 axis and disrupting the interplay between macrophages and tumor cells attenuates muscle wasting. Collectively, this study identifies a feedforward loop between pancreatic cancer cells and macrophages, underlying the non-autonomous activation of TWEAK secretion from tumor cells thereby providing promising therapeutic targets for pancreatic cancer cachexia.
摘要：
由于治疗选择有限，恶病质仍然是癌症患者的主要挑战。表征肿瘤细胞和免疫微环境之间的相互作用可能有助于识别癌症恶病质的潜在治疗靶点。本研究探索了巨噬细胞在通过促进肿瘤细胞分泌TWEAK（肿瘤坏死因子样凋亡弱诱导剂）从而促进胰腺癌诱导的肌肉萎缩中的关键作用。进一步研究表明，巨噬细胞的减少逆转了肿瘤细胞诱导的肌肉退化。巨噬细胞通过CCL5/TRAF6/NF-κB途径诱导TWEAK的非自主分泌。TWEAK通过激活MuRF1启动的肌肉重塑来促进肌肉萎缩。值得注意的是，肿瘤细胞通过CCL2/CCR2轴募集巨噬细胞并对其重新编程，而破坏巨噬细胞和肿瘤细胞之间的相互作用可减轻肌肉萎缩。总的来说，本文确定了胰腺癌细胞和巨噬细胞之间的前馈环路，该环路是肿瘤细胞中TWEAK分泌的非自主激活的基础，从而为胰腺癌恶病质提供了有希望的治疗靶点。
Jun 10,2024 Volume 42，Issue 6，p915-1132
2024年6月，Cancer Cell共发表23篇文章，其中包括Voices 1篇，Commentaries 3篇，Previews 4篇，Spotlight 1篇，Review 1篇，Articles 9篇，Editorial note 1篇，Corrections 3篇。
1.Distinct roles of TREM2 in central nervous system cancers and peripheral cancers
TREM2在中枢神经系统癌症和外周神经系统癌症中的不同作用
中山大学附属第一医院神经外科
Summary
Glioblastomas (GBM) are incurable central nervous system (CNS) cancers characterized by substantial myeloid cell infiltration. Whether myeloid cell-directed therapeutic targets identified in peripheral non-CNS cancers are applicable to GBM requires further study. Here, we identify that the critical immunosuppressive target in peripheral cancers, triggering receptor expressed on myeloid cells-2 (TREM2), is immunoprotective in GBM. Genetic or pharmacological TREM2 deficiency promotes GBM progression in vivo. Single-cell and spatial sequencing reveals downregulated TREM2 in GBM-infiltrated myeloid cells. TREM2 negatively correlates with immunosuppressive myeloid and T cell exhaustion signatures in GBM. We further demonstrate that during GBM progression, CNS-enriched sphingolipids bind TREM2 on myeloid cells and elicit antitumor responses. Clinically, high TREM2 expression in myeloid cells correlates with better survival in GBM. Adeno-associated virus-mediated TREM2 overexpression impedes GBM progression and synergizes with anti-PD-1 therapy. Our results reveal distinct functions of TREM2 in CNS cancers and support organ-specific myeloid cell remodeling in cancer immunotherapy.
摘要：
胶质母细胞瘤（GBM）是不可治愈的中枢神经系统（CNS）癌症，其特征是大量髓系细胞浸润。外周非中枢神经系统肿瘤中确定的髓系细胞靶向的治疗靶点是否适用于GBM需要进一步研究。本研究确定了外周神经系统肿瘤的关键免疫抑制靶点——髓样细胞表达受体-2（TREM2），在GBM中具有免疫保护作用。遗传性或药理水平的TREM2缺乏可促进体内GBM进展。单细胞和空间测序显示GBM浸润的髓系细胞中TREM2下调。TREM2与GBM中免疫抑制性髓细胞和T细胞衰竭信号负相关。研究者进一步证明，在GBM进展过程中，中枢神经系统富含的神经鞘脂与髓系细胞上的TREM2结合，从而引发抗肿瘤反应。临床上，髓系细胞中TREM2的高表达与GBM的更好的生存期相关。腺相关病毒介导的TREM2过表达可阻碍GBM进展，并与抗PD-1治疗具有协同作用。本研究的结果揭示了TREM2在中枢神经系统癌症中的独特功能，并支持癌症免疫治疗中的器官特异性髓样细胞重塑。
2.Tumor cells impair immunological synapse formation via central nervous system-enriched metabolite
肿瘤细胞通过中枢神经系统富集的代谢物影响免疫突触的形成
中山大学孙逸仙纪念医院医学研究中心
Summary
Tumors employ various strategies to evade immune surveillance. Central nervous system (CNS) has multiple features to restrain immune response. Whether tumors and CNS share similar programs of immunosuppression is elusive. Here, we analyze multi-omics data of tumors from HER2+ breast cancer patients receiving trastuzumab and anti-PD-L1 antibody and find that CNS-enriched N-acetyltransferase 8-like (NAT8L) and its metabolite N-acetylaspartate (NAA) are overexpressed in resistant tumors. In CNS, NAA is released during brain inflammation. NAT8L attenuates brain inflammation and impairs anti-tumor immunity by inhibiting cytotoxicity of natural killer (NK) cells and CD8+ T cells via NAA. NAA disrupts the formation of immunological synapse by promoting PCAF-induced acetylation of lamin A-K542, which inhibits the integration between lamin A and SUN2 and impairs polarization of lytic granules. We uncover that tumor cells mimic the anti-inflammatory mechanism of CNS to evade anti-tumor immunity and NAT8L is a potential target to enhance efficacy of anti-cancer agents.
摘要：
肿瘤采用多种策略来逃避免疫监视。中枢神经系统（CNS）具有多种抑制免疫反应的特征。肿瘤和中枢神经系统是否存在相似的免疫抑制程序尚不清楚。在这里，研究者分析了接受曲妥珠单抗和抗PD-L1抗体的HER2+乳腺癌患者的肿瘤多组学数据，发现富集于中枢神经系统的N-乙酰转移酶8样（NAT8L）及其代谢产物N-乙酰天冬氨酸（NAA）在耐药肿瘤中过表达。在中枢神经系统中，NAA在大脑发生炎症时释放。NAT8L通过NAA抑制自然杀伤细胞和CD8+ T细胞的细胞毒性来减轻脑部炎症并损害抗肿瘤免疫。NAA通过促进PCAF(蛋白质乙酰转移酶)诱导的核纤层蛋白A-K542的乙酰化来破坏免疫突触的形成，这抑制了核纤层蛋白A和SUN2（一种与核膜和细胞骨架相关的蛋白质）之间的整合并削弱了溶解颗粒的极化。总之，该研究发现了肿瘤细胞可模拟中枢神经系统的抗炎机制来逃避抗肿瘤免疫，并且NAT8L是增强抗癌药物功效的潜在靶标。
3.Integrated single cell analysis reveals co-evolution of malignant B cells and tumor micro-environment in transformed follicular lymphoma
整合单细胞分析揭示了转化滤泡性淋巴瘤中恶性B细胞和肿瘤微环境的共同进化
法国圣克劳德居里研究所
Summary
Histological transformation of follicular lymphoma (FL) to aggressive forms is associated with poor outcome. Phenotypic consequences of this evolution and its impact on the tumor microenvironment (TME) remain unknown. We perform single-cell whole genome sequencing (scWGS) and transcriptome sequencing (scWTS) of 11 paired pre/post-transformation patient samples and scWTS of additional samples from patients without transformation. Our analysis reveals evolutionary dynamics of transformation at single-cell resolution, highlighting a shifting TME landscape, with an emerging immune-cell exhaustion signature, co-evolving with the shifting malignant B phenotype in a regulatory ecosystem. Integration of scWGS and scWTS identifies malignant cell pathways upregulated during clonal tumor evolution. Using multi-color immunofluorescence, we transfer these findings to a TME-based transformation biomarker, subsequently validated in two independent pretreatment cohorts. Taken together, our results provide a comprehensive view of the combined genomic and phenotypic evolution of malignant cells during transformation and shifting crosstalk between malignant cells and the TME.
摘要：
滤泡性淋巴瘤（FL）向侵袭性形式的组织学转化与不良预后相关。这种进化的表型结果及其对肿瘤微环境（TME）的影响仍然未知。研究者对11对转化前/后患者样本和来自未转化患者的额外样本进行单细胞全基因组测序(scWGS)和转录组测序(scWTS)。上述分析揭示了单细胞分辨率下转化的进化动力学，突出了TME景观的变化，即出现了免疫细胞耗竭信号，这些特征在与恶性B表型的转变调控生态系统中共同进化。scWGS和scWTS的整合确定了克隆性肿瘤进化过程中上调的恶性细胞途径。使用多色免疫荧光，研究者将这些发现转化到基于TME的转化生物标志物，随后在两个独立的治疗前队列中得到验证。综上所述，该研究结果展示了转化期间恶性细胞的基因组和表型联合进化的概况，以及恶性细胞与肿瘤微环境之间变化的相互作用。。
4.The temporal progression of lung immune remodeling during breast cancer metastasis
乳腺癌转移过程中肺部免疫重建的时间进程
美国斯坦福大学病理学系
Summary
Tumor metastasis requires systemic remodeling of distant organ microenvironments that impacts immune cell phenotypes, population structure, and intercellular communication. However, our understanding of immune phenotypic dynamics in the metastatic niche remains incomplete. Here, we longitudinally assayed lung immune transcriptional profiles in the polyomavirus middle T antigen (PyMT) and 4T1 metastatic breast cancer models from primary tumorigenesis, through pre-metastatic niche formation, to the final stages of metastatic outgrowth at single-cell resolution. Computational analyses of these data revealed a TLR-NFκB inflammatory program enacted by both peripherally derived and tissue-resident myeloid cells that correlated with pre-metastatic niche formation and mirrored CD14+ “activated” myeloid cells in the primary tumor. Moreover, we observed that primary tumor and metastatic niche natural killer (NK) cells are differentially regulated in mice and human patient samples, with the metastatic niche featuring elevated cytotoxic NK cell proportions. Finally, we identified cell-type-specific dynamic regulation of IGF1 and CCL6 signaling during metastatic progression that represents anti-metastatic immunotherapy candidate pathways.
摘要：
肿瘤转移需要对远处器官微环境进行系统性的重塑，这会影响免疫细胞表型、群体结构和细胞间通讯。然而，目前对转移微环境中免疫表型动力学的理解仍不完整。研究者纵向分析了多瘤病毒中间T抗原（PyMT）和4T1转移性乳腺癌模型从原发性肿瘤发生，通过转移前微环境形成，到转移生长最终阶段的单细胞分辨率肺部免疫转录谱。对这些数据的计算分析揭示了一种由外周来源和组织驻留髓系细胞共同启动的TLR-NFκB炎症程序，该程序与转移前灶的形成相关，并反映了原发肿瘤中CD14+“活化”髓系细胞的情况。此外，研究者观察到，在小鼠和人类患者样本中，原发性肿瘤和转移性微环境自然杀伤（NK）细胞受到不同程度的调节，转移灶中细胞毒性NK细胞比例升高。最后，该研究确定了在转移进展过程中，IGF1和CCL6信号通路在特定细胞类型中的动态调控，这代表了抗转移性免疫治疗的候选途径。
5.Immunotherapy-activated T cells recruit and skew late-stage activated M1-like macrophages that are critical for therapeutic efficacy
免疫疗法激活的T细胞会招募并诱导晚期活化的M1样巨噬细胞，这些巨噬细胞对治疗效果至关重要
荷兰莱顿大学医学中心
Summary
Total tumor clearance through immunotherapy is associated with a fully coordinated innate and adaptive immune response, but knowledge on the exact contribution of each immune cell subset is limited. We show that therapy-induced intratumoral CD8+ T cells recruited and skewed late-stage activated M1-like macrophages, which were critical for effective tumor control in two different murine models of cancer immunotherapy. The activated CD8+ T cells summon these macrophages into the tumor and their close vicinity via CCR5 signaling. Exposure of non-polarized macrophages to activated T cell supernatant and tumor lysate recapitulates the late-stage activated and tumoricidal phenotype in vitro. The transcriptomic signature of these macrophages is also detected in a similar macrophage population present in human tumors and coincides with clinical response to immune checkpoint inhibitors. The requirement of a functional co-operation between CD8+ T cells and effector macrophages for effective immunotherapy gives warning to combinations with broad macrophage-targeting strategies.
摘要：
通过免疫疗法实现肿瘤完全清除与先天性和适应性免疫反应的充分协调有关，但目前对每个免疫细胞亚群的确切贡献了解有限。研究发现，在两种不同的小鼠癌症免疫治疗模型中，治疗诱导的肿瘤内CD8+ T细胞能够招募并诱导晚期活化的M1样巨噬细胞，这些巨噬细胞对于有效控制肿瘤至关重要。活化的CD8+ T细胞通过CCR5信号将这些巨噬细胞募集到肿瘤及其附近。体外将未极化的巨噬细胞暴露于活化的T细胞上清液和肿瘤裂解物再现了的晚期M1活化和抗肿瘤表型。在人类肿瘤中存在的类似巨噬细胞群中也检测到这些巨噬细胞的转录组标记，并且与对免疫检查点抑制剂的临床反应一致。有效免疫治疗需要CD8+ T细胞和效应巨噬细胞之间的功能性合作，这对广泛的巨噬细胞靶向策略的组合提供了警示作用。
6.Interruption of the intratumor CD8+ T cell: Treg crosstalk improves the efficacy of PD-1 immunotherapy
阻断肿瘤内CD8+ T细胞与调节性T细胞（Treg）间的相互作用可提高PD-1免疫治疗的疗效
美国加州大学欧文分校免疫研究所
Summary
PD-1 blockade unleashes potent antitumor activity in CD8+ T cells but can also promote immunosuppressive T regulatory (Treg) cells, which may worsen the response to immunotherapy. Tumor-Treg inhibition is a promising strategy to improve the efficacy of checkpoint blockade immunotherapy; however, our understanding of the mechanisms supporting tumor-Tregs during PD-1 immunotherapy is incomplete. Here, we show that PD-1 blockade increases tumor-Tregs in mouse models of melanoma and metastatic melanoma patients. Mechanistically, Treg accumulation is not caused by Treg-intrinsic inhibition of PD-1 signaling but depends on an indirect effect of activated CD8+ T cells. CD8+ T cells produce IL-2 and colocalize with Tregs in mouse and human melanomas. IL-2 upregulates the anti-apoptotic protein ICOS on tumor-Tregs, promoting their accumulation. Inhibition of ICOS signaling before PD-1 immunotherapy improves control over immunogenic melanoma. Thus, interrupting the intratumor CD8+ T cell:Treg crosstalk represents a strategy to enhance the therapeutic efficacy of PD-1 immunotherapy.
摘要：
PD-1阻断能够激发CD8+ T细胞强大的抗肿瘤活性，但也可能促进免疫抑制T调节（Treg）细胞的增殖，这可能会削弱免疫治疗的疗效。肿瘤Treg抑制是一种有望提高检查点阻断免疫治疗效果的策略；然而，研究者对PD-1免疫治疗期间促进肿瘤Tregs增殖的机制的理解尚不完整。本研究表明PD-1阻断增加了黑色素瘤和转移性黑色素瘤患者小鼠模型中的肿瘤Tregs。从机制上来说，Treg的积聚不是由Treg对PD-1信号的内在抑制引起的，而是依赖于活化的CD8+ T细胞的间接作用。在小鼠和人类黑色素瘤中，CD8+ T细胞产生IL-2并与Tregs共定位。IL-2上调肿瘤Tregs上的抗凋亡蛋白ICOS，从而促进其积聚。在PD-1免疫治疗前抑制ICOS信号可改善对免疫原性黑色素瘤的控制。因此，阻断肿瘤内CD8+ T细胞与Treg相互作用代表了一种增强PD-1免疫疗法疗效的策略。
7.Integrative molecular and spatial analysis reveals evolutionary dynamics and tumor-immune interplay of in situ and invasive acral melanoma
整合分子和空间分析揭示了原位和侵袭性肢端黑色素瘤的进化动力学和肿瘤免疫相互作用
北京大学第一医院
Summary
In acral melanoma (AM), progression from in situ (AMis) to invasive AM (iAM) leads to significantly reduced survival. However, evolutionary dynamics during this process remain elusive. Here, we report integrative molecular and spatial characterization of 147 AMs using genomics, bulk and single-cell transcriptomics, and spatial transcriptomics and proteomics. Vertical invasion from AMis to iAM displays an early and monoclonal seeding pattern. The subsequent regional expansion of iAM exhibits two distinct patterns, clonal expansion and subclonal diversification. Notably, molecular subtyping reveals an aggressive iAM subset featured with subclonal diversification, increased epithelial-mesenchymal transition (EMT), and spatial enrichment of APOE+/CD163+ macrophages. In vitro and ex vivo experiments further demonstrate that APOE+CD163+ macrophages promote tumor EMT via IGF1-IGF1R interaction. Adnexal involvement can predict AMis with higher invasive potential whereas APOE and CD163 serve as prognostic biomarkers for iAM. Altogether, our results provide implications for the early detection and treatment of AM.
摘要：
在肢端黑色素瘤（AM）中，从原位黑色素瘤（AMis）进展到侵袭性黑色素瘤（iAM）会导致生存率显著降低。然而，这一过程中的进化动力学仍不清楚。本文利用基因组学、整体和单细胞转录组学、空间转录组学和蛋白质组学，报道了147个AMs的综合分子和空间特征。从AMis到iAM的侵袭过程显示了早期的单克隆播种模式。iAM随后的区域扩展表现出两种不同的模式：克隆性扩张和亚克隆多样化。值得注意的是，分子分型揭示了一种侵袭性iAM亚群，其特征为亚克隆多样化、上皮-间质转化（EMT）增加以及APOE+/CD163+巨噬细胞的空间富集。体外和体内实验进一步证明，APOE+CD163+巨噬细胞通过IGF1-IGF1R相互作用促进肿瘤EMT。附件受累可以预测具有较高侵袭潜能的AMis，而APOE和CD163可以作为iAM的预后生物标志物。总之，该研究结果为AM的早期检测和治疗提供了启示。
8.Molecular subtypes of neuroendocrine carcinomas: A cross-tissue classification framework based on five transcriptional regulators
神经内分泌癌的分子亚型:基于五种转录调节因子的跨组织分类框架
中国科学院国家癌症中心
Summary
Neuroendocrine carcinomas (NECs) are extremely lethal malignancies that can arise at almost any anatomic site. Characterization of NECs is hindered by their rarity and significant inter- and intra-tissue heterogeneity. Herein, through an integrative analysis of over 1,000 NECs originating from 31 various tissues, we reveal their tissue-independent convergence and further unveil molecular divergence driven by distinct transcriptional regulators. Pan-tissue NECs are therefore categorized into five intrinsic subtypes defined by ASCL1, NEUROD1, HNF4A, POU2F3, and YAP1. A comprehensive portrait of these subtypes is depicted, highlighting subtype-specific transcriptional programs, genomic alterations, evolution trajectories, therapeutic vulnerabilities, and clinicopathological presentations. Notably, the newly discovered HNF4A-dominated subtype-H exhibits a gastrointestinal-like signature, wild-type RB1, unique neuroendocrine differentiation, poor chemotherapeutic response, and prevalent large-cell morphology. The proposal of uniform classification paradigm illuminates transcriptional basis of NEC heterogeneity and bridges the gap across different lineages and cytomorphological variants, in which context-dependent prevalence of subtypes underlies their phenotypic disparities
摘要：
神经内分泌癌（NECs）是一种非常致命的恶性肿瘤，几乎可以发生在任何部位。NECs因其稀有性和显著的组织间和组织内异质性，所以其特征不明。在本文中，通过对来自31种不同组织的超过1，000个NECs的综合分析，研究者揭示了它们跨越组织的共同特征，并进一步揭示了由不同转录调节因子驱动的分子差异。根据ASCL1、NEUROD1、HNF4A、POU2F3和YAP1的表达，将NEC分为五种固有亚型。对这些亚型进行了全面的描述，强调了亚型特异性转录程序、基因组改变、进化轨迹、治疗弱点和临床病理表现。值得注意的是，新发现的HNF4A主导的H亚型表现出胃肠样特征、RB1野生型、独特的神经内分泌分化、较差的化疗反应和普遍的大细胞形态学。统一分类范式的提出阐明了NEC异质性的转录基础，并弥合了不同谱系和细胞形态学变异之间的差距。
9.Olfactory neuroblastoma mimics molecular heterogeneity and lineage trajectories of small-cell lung cancer
嗅神经母细胞瘤模拟小细胞肺癌的分子异质性和谱系轨迹
美国杜克大学头颈外科
Summary
The olfactory epithelium undergoes neuronal regeneration from basal stem cells and is susceptible to olfactory neuroblastoma (ONB), a rare tumor of unclear origins. Employing alterations in Rb1/Trp53/Myc (RPM), we establish a genetically engineered mouse model of high-grade metastatic ONB exhibiting a NEUROD1+ immature neuronal phenotype. We demonstrate that globose basal cells (GBCs) are a permissive cell of origin for ONB and that ONBs exhibit cell fate heterogeneity that mimics normal GBC developmental trajectories. ASCL1 loss in RPM ONB leads to emergence of non-neuronal histopathologies, including a POU2F3+ microvillar-like state. Similar to small-cell lung cancer (SCLC), mouse and human ONBs exhibit mutually exclusive NEUROD1 and POU2F3-like states, an immune-cold tumor microenvironment, intratumoral cell fate heterogeneity comprising neuronal and non-neuronal lineages, and cell fate plasticity—evidenced by barcode-based lineage tracing and single-cell transcriptomics. Collectively, our findings highlight conserved similarities between ONB and neuroendocrine tumors with significant implications for ONB classification and treatment.
摘要：
嗅觉上皮经历基底干细胞的神经元再生，易患嗅神经母细胞瘤（ONB），这是一种罕见的起源不明的肿瘤。利用Rb1/Trp53/Myc （RPM）的改变，研究者建立了一个高度转移性ONB的基因工程小鼠模型，表现出NEUROD1+未成熟神经元表型。研究者证明了球状基底细胞（GBCs）是ONB起源的一类细胞，并且ONBs表现出模拟正常GBC发育轨迹的细胞命运异质性。RPM ONB中ASCL1缺失导致非神经元组织病理学出现，包括POU2F3+微绒毛样状态。通过谱系追踪和单细胞转录组学证实，与小细胞肺癌类似，小鼠和人类ONBs表现出相互排斥的NEUROD1和POU2F3样状态，冷肿瘤免疫微环境，包括神经元和非神经元谱系的肿瘤内细胞命运异质性，以及细胞命运可塑性。总的来说，该研究的发现强调了ONB和神经内分泌肿瘤之间的保守相似性，对ONB分类和治疗具有重要意义。
汇报人：周菁
导师：刘世喜
审核：冯兰、任建君
