华西耳鼻喉前沿学术速递——文献导读（第49期）

【Cancer Cell】2024年7-9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7-9月一共发表49篇文章，包括Commentaries 8篇，Previews 11篇，Article 22篇，Corrections 4篇，Letters 1篇，Report 1篇，Perspective 1篇，Review 1篇。

Jul 08, 2024 Volume 42，Issue 7，p1133-1314

2024年7月，Cancer Cell共发表18篇文章，其中包括Commentaries 4篇；Review 1篇；Previews 4篇；Correction 1篇；Articles 7篇；Report 1篇。

1、IRF4 requires ARID1A to establish plasma cell identity in multiple myeloma

IRF4在多发性骨髓瘤中建立浆细胞特征有赖于ARID1A

美国国立卫生研究院癌症研究中心

Summary

Multiple myeloma (MM) is an incurable plasma cell malignancy that exploits transcriptional networks driven by IRF4. We employ a multi-omics approach to discover IRF4 vulnerabilities, integrating functional genomics screening, spatial proteomics, and global chromatin mapping. ARID1A, a member of the SWI/SNF chromatin remodeling complex, is required for IRF4 expression and functionally associates with IRF4 protein on chromatin. Deleting Arid1a in activated murine B cells disrupts IRF4-dependent transcriptional networks and blocks plasma cell differentiation. Targeting SWI/SNF activity leads to rapid loss of IRF4-target gene expression and quenches global amplification of oncogenic gene expression by MYC, resulting in profound toxicity to MM cells. Notably, MM patients with aggressive disease bear the signature of SWI/SNF activity, and SMARCA2/4 inhibitors remain effective in immunomodulatory drug (IMiD)-resistant MM cells. Moreover, combinations of SWI/SNF and MEK inhibitors demonstrate synergistic toxicity to MM cells, providing a promising strategy for relapsed/refractory disease.

摘要

多发性骨髓瘤（MM）是一种由IRF4驱动的转录网络介导的不可治愈的浆细胞恶性肿瘤。本研究采用多组学方法，结合功能基因组学筛选、空间蛋白质组学和全染色质图谱，以揭示IRF4的脆弱性。ARID1A作为SWI/SNF染色质重塑复合体的一员，对于IRF4的表达至关重要，且其在染色质水平上与IRF4蛋白功能性地相互作用。在活化的鼠B细胞中敲除Arid1a会破坏依赖IRF4的转录网络，并阻止浆细胞分化。靶向SWI/SNF活性导致IRF4靶基因表达迅速下降，并通过抑制MYC驱动的致癌基因表达的全局扩增，对MM细胞产生显著的细胞毒性。值得注意的是，侵袭性多发性骨髓瘤患者带有SWI/SNF活性的特征，且SMARCA2/4抑制剂在免疫调节药物耐药的MM细胞中仍然有效。此外，SWI/SNF和MEK抑制剂的联合应用显示出对MM细胞的协同毒性作用，为复发/难治性MM提供了一种有前景的治疗策略。

2、Intratumoral immune triads are required for immunotherapy-mediated elimination of solid tumors

肿瘤内免疫三联体是免疫疗法介导的实体瘤消除所必需的

美国纪念斯隆-凯特琳癌症中心

Summary

Tumor-specific CD8+ T cells are frequently dysfunctional and unable to halt tumor growth. We investigated whether tumor-specific CD4+ T cells can be enlisted to overcome CD8+ T cell dysfunction within tumors. We find that the spatial positioning and interactions of CD8+ and CD4+ T cells, but not their numbers, dictate anti-tumor responses in the context of adoptive T cell therapy as well as immune checkpoint blockade (ICB): CD4+ T cells must engage with CD8+ T cells on the same dendritic cell during the effector phase, forming a three-cell-type cluster (triad) to license CD8+ T cell cytotoxicity and cancer cell elimination. When intratumoral triad formation is disrupted, tumors progress despite equal numbers of tumor-specific CD8+ and CD4+ T cells. In patients with pleural mesothelioma treated with ICB, triads are associated with clinical responses. Thus, CD4+ T cells and triads are required for CD8+ T cell cytotoxicity during the effector phase and tumor elimination.

摘要

肿瘤特异性CD8+ T细胞常表现出功能障碍，无法有效抑制肿瘤生长。本研究旨在探讨肿瘤特异性CD4+ T细胞是否能够被动员以克服肿瘤微环境中CD8+ T细胞的功能缺陷。研究结果表明，CD8+ T细胞和CD4+ T细胞的空间定位及其相互作用，而非它们的数量，决定了T细胞过继免疫疗法和免疫检查点阻断(ICB)治疗中的抗肿瘤反应：在效应阶段，CD4+ T细胞需与CD8+ T细胞在同一树突状细胞上相互作用，形成由三种类型细胞组成的三角簇(三联体)，以此激活CD8+ T细胞的细胞毒性作用并促进癌细胞消除。当肿瘤内三联体的形成受到干扰，即使肿瘤特异性CD8+ T细胞和CD4+ T细胞数量保持不变，肿瘤仍会进展。在采用ICB治疗的胸膜间皮瘤患者中，三联体的形成与临床反应显著相关。因此，CD4+ T细胞和三联体在效应阶段CD8+ T细胞介导的细胞毒性和肿瘤清除过程中发挥着关键作用。

3、Multi-scale signaling and tumor evolution in high-grade gliomas

高级别胶质瘤中的多尺度信号和肿瘤演变

美国华盛顿大学医学部

Summary

Although genomic anomalies in glioblastoma (GBM) have been well studied for over a decade, its 5-year survival rate remains lower than 5%. We seek to expand the molecular landscape of high-grade glioma, composed of IDH-wildtype GBM and IDH-mutant grade 4 astrocytoma, by integrating proteomic, metabolomic, lipidomic, and post-translational modifications (PTMs) with genomic and transcriptomic measurements to uncover multi-scale regulatory interactions governing tumor development and evolution. Applying 14 proteogenomic and metabolomic platforms to 228 tumors (212 GBM and 16 grade 4 IDH-mutant astrocytoma), including 28 at recurrence, plus 18 normal brain samples and 14 brain metastases as comparators, reveals heterogeneous upstream alterations converging on common downstream events at the proteomic and metabolomic levels and changes in protein-protein interactions and glycosylation site occupancy at recurrence. Recurrent genetic alterations and phosphorylation events on PTPN11 map to important regulatory domains in three dimensions, suggesting a central role for PTPN11 signaling across high-grade gliomas.

摘要

尽管胶质母细胞瘤（GBM）的基因组异常已历经十数年的深入研究，但其5年生存率仍不足5%。本研究旨在通过整合蛋白质组学、代谢组学、脂质组学以及翻译后修饰（PTMs）技术，将其与基因组学和转录组学数据相结合，以扩充高级别胶质瘤（包括IDH野生型GBM和IDH突变型4级星形细胞瘤）的分子图谱。这一整合策略旨在揭示调控肿瘤发生与进化的多尺度调控网络。通过对228个肿瘤样本（212个GBM和16个IDH突变型4级星形细胞瘤）以及28个复发肿瘤样本、18个正常脑组织样本和14个脑转移样本进行14个蛋白质组和代谢组平台分析，发现了异质性上游改变在蛋白质组学和代谢组学水平上趋向于共同下游事件，并在复发肿瘤中观察到蛋白质-蛋白质相互作用和糖基化位点占位的变化。复发性基因变异和PTPN11上的磷酸化事件在三维空间中对应于关键调控域，提示PTPN11信号通路在高级别胶质瘤中起着核心作用。

4、Advancing presurgical non-invasive molecular subgroup prediction in medulloblastoma using artificial intelligence and MRI signatures

使用人工智能和MRI信号推进髓母细胞瘤术前非侵入性分子亚群预测

安徽省生物医学影像与智能处理重点实验室，北京天坛医院

Summary

Global investigation of medulloblastoma has been hindered by the widespread inaccessibility of molecular subgroup testing and paucity of data. To bridge this gap, we established an international molecularly characterized database encompassing 934 medulloblastoma patients from thirteen centers across China and the United States. We demonstrate how image-based machine learning strategies have the potential to create an alternative pathway for non-invasive, presurgical, and low-cost molecular subgroup prediction in the clinical management of medulloblastoma. Our robust validation strategies—including cross-validation, external validation, and consecutive validation—demonstrate the model’s efficacy as a generalizable molecular diagnosis classifier. The detailed analysis of MRI characteristics replenishes the understanding of medulloblastoma through a nuanced radiographic lens. Additionally, comparisons between East Asia and North America subsets highlight critical management implications. We made this comprehensive dataset, which includes MRI signatures, clinicopathological features, treatment variables, and survival data, publicly available to advance global medulloblastoma research.

摘要

全球髓母细胞瘤研究的进展受到了分子亚群检测的普及性限制以及数据稀缺性的制约。为填补这一空白，本研究构建了一个国际分子特征数据库，汇集了中国和美国13个中心共934例髓母细胞瘤患者的详细资料。本研究展示了基于影像学的机器学习策略在髓母细胞瘤临床管理中，为非侵入性、术前以及低成本分子亚群预测提供了潜在的替代方案。本研究采用了一系列稳健的验证策略，包括交叉验证、外部验证和连续验证，这些策略验证了该模型作为一种通用分子诊断分类器的有效性。MRI特征的深入分析通过细致入微的影像学视角，进一步丰富了我们对髓母细胞瘤的理解。此外，东亚和北美亚组之间的比较揭示了管理策略中的关键差异。本研究已将包含MRI特征、临床病理特征、治疗变量和生存数据在内的全面数据集公开，以推进全球范围内对髓母细胞瘤研究。

5、Neoadjuvant SHR-1701 with or without chemotherapy in unresectable stage III non-small-cell lung cancer: A proof-of-concept, phase 2 trial

不可切除的III期非小细胞肺癌的新辅助SHR-1701联合或不联合化疗:一项概念验证2期试验

南方医科大学广东省人民医院

Summary

We conducted a proof-of-concept, phase 2 trial to assess neoadjuvant SHR-1701 with or without chemotherapy, followed by surgery or radiotherapy, and then consolidation SHR-1701 in unresectable stage III non-small-cell lung cancer (NSCLC). In the primary cohort of patients receiving neoadjuvant combination therapy (n = 97), both primary endpoints were met, with a post-induction objective response rate of 58% (95% confidence interval [CI] 47–68) and an 18-month event-free survival (EFS) rate of 56.6% (95% CI 45.2–66.5). Overall, 27 (25%) patients underwent surgery; all achieved R0 resection. Among them, 12 (44%) major pathological responses and seven (26%) pathological complete responses were recorded. The 18-month EFS rate was 74.1% (95% CI 53.2–86.7) in surgical patients and 57.3% (43.0–69.3) in radiotherapy-treated patients. Neoadjuvant SHR-1701 with chemotherapy, followed by surgery or radiotherapy, showed promising efficacy with a tolerable safety profile in unresectable stage III NSCLC. Surgical conversion was feasible in a notable proportion of patients and associated with better survival outcomes.

摘要

本研究进行了一项概念验证的II期临床试验，旨在评估在不可切除的III期非小细胞肺癌（NSCLC）患者的新辅助治疗阶段使用SHR-1701联合或不联合化疗，继之以手术或放疗，再实施SHR-1701巩固治疗的疗效。在纳入新辅助联合治疗组的患者队列中（n=97），两个主要研究终点均得以实现，诱导治疗后客观缓解率为58% (95%可信区间[CI]47–68)，18个月无事件生存率(EFS)为56.6%(95% CI 45.2–66.5)。总的来说，27名(25%)患者接受了手术；所有患者实现R0切除。其中，12名（44%）患者记录到主要病理缓解，7名（26%）患者达到病理完全缓解。手术患者的18个月EFS率为74.1%(95% CI 53.2–86.7)，而接受放疗的患者为57.3%(43.0–69.3)。在不可切除的III期非小细胞肺癌中，新辅助SHR-1701联合化疗，随后手术或放疗展示了良好的疗效和可耐受的安全性。相当比例的患者实现了手术转化，并伴随更佳的生存结果。

6、Spatiotemporal single-cell analysis decodes cellular dynamics underlying different responses to immunotherapy in colorectal cancer

时空单细胞分析解码结直肠癌免疫治疗不同反应的细胞动力学

北京大学生命科学学院

Summary

Expanding the efficacy of immune checkpoint blockade (ICB) in colorectal cancer (CRC) presses for a comprehensive understanding of treatment responsiveness. Here, we analyze multiple sequential single-cell samples from 22 patients undergoing PD-1 blockade to map the evolution of local and systemic immunity of CRC patients. In tumors, we identify coordinated cellular programs exhibiting distinct response associations. Specifically, exhausted T (Tex) or tumor-reactive-like CD8+ T (Ttr-like) cells are closely related to treatment efficacy, and Tex cells show correlated proportion changes with multiple other tumor-enriched cell types following PD-1 blockade. In addition, we reveal the less-exhausted phenotype of blood-associated Ttr-like cells in tumors and find that their higher abundance suggests better treatment outcomes. Finally, a higher major histocompatibility complex (MHC) II-related signature in circulating CD8+ T cells at baseline is linked to superior responses. Our study provides insights into the spatiotemporal cellular dynamics following neoadjuvant PD-1 blockade in CRC.

摘要

为了提升免疫检查点阻断（ICB）治疗在结直肠癌（CRC）中的疗效，对治疗反应性的全面认识至关重要。本研究分析了22名接受PD-1阻断治疗的患者的多个连续单细胞样本，以绘制CRC患者局部和全身免疫的演变图谱。本研究在肿瘤中识别出与不同反应关联的协同细胞程序。具体来说，耗竭性T（Tex）细胞或类似肿瘤反应性CD8+ T（Ttr-like）细胞与治疗效果密切相关，并且Tex细胞在PD-1阻断后，其比例变化与多种肿瘤富集细胞类型存在显著相关性。此外，本研究揭示了肿瘤中血源性Ttr样细胞的低耗竭表型，并发现其较高丰度与更佳的治疗结果相关。最后，发现在基线状态下循环CD8+ T细胞中MHC II相关标志物的表达水平与更优的治疗反应性呈正相关。本研究为结直肠癌患者接受新辅助PD-1阻断治疗后的时空细胞动力学提供了见解。

7、Anti-tumor efficacy of HRS-4642 and its potential combination with proteasome inhibition in KRAS G12D-mutant cancer

HRS-4642 的抗肿瘤功效及其与蛋白酶体抑制剂联合治疗 KRAS G12D 突变癌症的潜力

同济大学医学院附属上海市肺科医院

Summary

KRAS G12D is the most frequently mutated oncogenic KRAS subtype in solid tumors and remains undruggable in clinical settings. Here, we developed a high affinity, selective, long-acting, and non-covalent KRAS G12D inhibitor, HRS-4642, with an affinity constant of 0.083 nM. HRS-4642 demonstrated robust efficacy against KRAS G12D-mutant cancers both in vitro and in vivo. Importantly, in a phase 1 clinical trial, HRS-4642 exhibited promising anti-tumor activity in the escalating dosing cohorts. Furthermore, the sensitization and resistance spectrum for HRS-4642 was deciphered through genome-wide CRISPR-Cas9 screening, which unveiled proteasome as a sensitization target. We further observed that the proteasome inhibitor, carfilzomib, improved the anti-tumor efficacy of HRS-4642. Additionally, HRS-4642, either as a single agent or in combination with carfilzomib, reshaped the tumor microenvironment toward an immune-permissive one. In summary, this study provides potential therapies for patients with KRAS G12D-mutant cancers, for whom effective treatments are currently lacking.

摘要

KRAS G12D是实体瘤中最常见的突变致癌KRAS亚型，在临床上仍然不可治疗。本研究开发了一种高亲和力、选择性、长效、非共价的KRAS G12D抑制剂HRS-4642，其亲和常数为0.083 nM。HRS-4642在体外及体内实验中均展现出对KRAS G12D突变肿瘤的显著抑制效果。重要的是，在一项1期临床试验中，HRS-4642在剂量递增的受试者群体中展现出良好的抗肿瘤活性。此外，通过全基因组CRISPR-Cas9筛选破译了HRS-4642的致敏和耐药谱，揭示了蛋白酶体是致敏靶标。研究进一步发现，蛋白酶体抑制剂卡非佐米与HRS-4642联用可显著增强其抗肿瘤疗效。此外，HRS-4642无论是作为单一药物还是与卡非佐米联合使用，均能重塑肿瘤微环境，使其更加有利于免疫系统发挥作用。总之，这项研究为目前缺乏有效治疗的KRAS G12D突变癌症患者提供了潜在的治疗策略。

Aug 12, 2024，Volume 42，Issue 8，p1315-1472

2024年8月，Cancer Cell共发表16篇文章，其中包括Commentaries 2篇；Previews 4篇；Articles 8篇；Corrections 2篇。

1、Targeting the mSWI/SNF complex in POU2F-POU2AF transcription factor-driven malignancies

靶向POU2F-POU2AF转录因子驱动的恶性肿瘤中的mSWI/SNF复合物

美国密歇根大学

Summary

The POU2F3-POU2AF2/3 transcription factor complex is the master regulator of the tuft cell lineage and tuft cell-like small cell lung cancer (SCLC). Here, we identify a specific dependence of the POU2F3 molecular subtype of SCLC (SCLC-P) on the activity of the mammalian switch/sucrose non-fermentable (mSWI/SNF) chromatin remodeling complex. Treatment of SCLC-P cells with a proteolysis targeting chimera (PROTAC) degrader of mSWI/SNF ATPases evicts POU2F3 and its coactivators from chromatin and attenuates downstream signaling. B cell malignancies which are dependent on the POU2F1/2 cofactor, POU2AF1, are also sensitive to mSWI/SNF ATPase degraders, with treatment leading to chromatin eviction of POU2AF1 and IRF4 and decreased IRF4 signaling in multiple myeloma cells. An orally bioavailable mSWI/SNF ATPase degrader significantly inhibits tumor growth in preclinical models of SCLC-P and multiple myeloma without signs of toxicity. This study suggests that POU2F-POU2AF-driven malignancies have an intrinsic dependence on the mSWI/SNF complex, representing a therapeutic vulnerability.

摘要

POU2F3-POU2AF2/3转录因子复合物是簇状细胞谱系和簇状细胞样小细胞肺癌(SCLC)的关键调控因子。本研究揭示了SCLC中POU2F3亚型（SCLC-P）对哺乳动物SWI/SNF染色质重塑复合物活性的特异性依赖性。通过使用针对SWI/SNF ATP酶的蛋白酶体靶向降解剂（PROTAC）处理SCLC-P细胞，可以有效地从染色质中去除POU2F3及其协同激活因子，进而减弱下游信号传导。依赖POU2F1/2辅助因子POU2AF1的B细胞恶性肿瘤也对mSWI/SNF ATP酶降解剂敏感，治疗可导致POU2AF1和IRF4从染色质中移除，并降低多发性骨髓瘤细胞中的IRF4信号传导。一种口服生物利用度高的mSWI/SNF ATP酶降解剂在SCLC-P和多发性骨髓瘤的临床前模型中显著抑制肿瘤生长，且无毒性反应。本研究结果表明，由POU2F-POU2AF驱动的恶性肿瘤对mSWI/SNF复合物存在固有依赖，这一特性可能成为治疗上的潜在弱点。

2、Mammalian SWI/SNF complex activity regulates POU2F3 and constitutes a targetable dependency in small cell lung cancer

哺乳动物SWI/SNF复合物活性调节POU2F3并在小细胞肺癌中构成靶向依赖性

美国哈佛医学院

Summary

Small cell lung cancers (SCLCs) are composed of heterogeneous subtypes marked by lineage-specific transcription factors, including ASCL1, NEUROD1, and POU2F3. POU2F3-positive SCLCs, ∼12% of all cases, are uniquely dependent on POU2F3 itself; as such, approaches to attenuate POU2F3 expression may represent new therapeutic opportunities. Here using genome-scale screens for regulators of POU2F3 expression and SCLC proliferation, we define mSWI/SNF complexes as top dependencies specific to POU2F3-positive SCLC. Notably, chemical disruption of mSWI/SNF ATPase activity attenuates proliferation of all POU2F3-positive SCLCs, while disruption of non-canonical BAF (ncBAF) via BRD9 degradation is effective in pure non-neuroendocrine POU2F3-SCLCs. mSWI/SNF targets to and maintains accessibility over gene loci central to POU2F3-mediated gene regulatory networks. Finally, clinical-grade pharmacologic disruption of SMARCA4/2 ATPases and BRD9 decreases POU2F3-SCLC tumor growth and increases survival in vivo. These results demonstrate mSWI/SNF-mediated governance of the POU2F3 oncogenic program and suggest mSWI/SNF inhibition as a therapeutic strategy for POU2F3-positive SCLCs.

摘要

小细胞肺癌(SCLCs)由谱系特异性转录因子标记的异质性亚型组成，包括ASCL1、NEUROD1和POU2F3。POU2F3阳性的小细胞肺癌，占所有病例的12%，其独特性依赖POU2F3本身；因此，降低POU2F3表达的方法可能代表了新的治疗机会。在本研究中，通过全基因组筛选来确定POU2F3表达和SCLC增殖的调控因子，将mSWI/SNF复合物定义为POU2F3阳性SCLC的特异性的顶级依赖性。值得注意的是，mSWI/SNF ATPase活性的化学破坏减弱了所有POU2F3阳性小细胞肺癌的增殖，而通过BRD9降解破坏非典型BAF (ncBAF)则对纯非神经内分泌POU2F3-小细胞肺癌有效。mSWI/SNF靶向并维持了对POU2F3介导的基因调控网络中关键基因座的可及性。最后，临床级药物对SMARCA4/2 ATP酶和BRD9的破坏降低了POU2F3-SCLC的肿瘤生长并提高体内生存率。这些结果表明mSWI/SNF介导的POU2F3致癌程序的控制，并建议将mSWI/SNF抑制作为POU2F3阳性SCLC的一种治疗策略。

3、CCL19-producing fibroblasts promote tertiary lymphoid structure formation enhancing anti-tumor IgG response in colorectal cancer liver metastasis

产生CCL19的成纤维细胞促进三级淋巴结构形成，增强结直肠癌肝转移中的抗肿瘤IgG反应

中山大学附属第一医院肝胆胰外科中心

Summary

Tertiary lymphoid structures (TLSs) are associated with enhanced immunity in tumors. However, their formation and functions in colorectal cancer liver metastasis (CRLM) remain unclear. Here, we reveal that intra- and peri-tumor mature TLSs (TLS+) are associated with improved clinical outcomes than TLS− tumors. Using single-cell-RNA-sequencing and spatial-enhanced-resolution-omics-sequencing (Stereo-seq), we reveal that TLS+ tumors are enriched with IgG+ plasma cells (PCs), while TLS− tumors are characterized with IgA+ PCs. By generating TLS-associated PC-derived monoclonal antibodies in vitro, we show that TLS-PCs secrete tumor-targeting antibodies. As the proof-of-concept, we demonstrate the anti-tumor activities of TLS-PC-mAb6 antibody in humanized mouse model of colorectal cancer. We identify a fibroblast lineage secreting CCL19 that facilitates lymphocyte trafficking to TLSs. CCL19 treatment promotes TLS neogenesis and prevents tumor growth in mice. Our data uncover the central role of CCL19+ fibroblasts in TLS formation, which in turn generates therapeutic antibodies to restrict CRLM

摘要

三级淋巴结构(TLSs)与肿瘤免疫增强相关。然而，它们在结直肠癌肝转移(CRLM)中的形成和功能仍不清楚。本文揭示了肿瘤内和肿瘤周围的成熟TLS(TLS+)比TLS-肿瘤具有更好的临床结果。通过单细胞RNA测序和空间增强分辨率组学测序(Stereo-seq )，本研究发现TLS+肿瘤富含IgG+浆细胞(PCs)，而TLS-肿瘤以IgA+ PCs为特征。通过体外产生TLS相关的PC衍生单克隆抗体，本研究表明TLS-PC分泌肿瘤靶向抗体。作为概念证明，本研究在结肠直肠癌的人源化小鼠模型中证明了TLS-PC-mAb6抗体的抗肿瘤活性。本研究鉴定了一种分泌CCL19的成纤维细胞谱系，它促进淋巴细胞向TLSs迁移。CCL19治疗促进小鼠TLS新生和抑制肿瘤生长。本研究的数据揭示了CCL19+成纤维细胞在TLS形成中的核心作用，进而产生治疗性抗体以限制CRLM。

4、Integrative plasma and fecal metabolomics identify functional metabolites in adenoma-colorectal cancer progression and as early diagnostic biomarkers

综合血浆和粪便代谢组学鉴定腺瘤-结直肠癌进展中的功能性代谢物并作为早期诊断生物标志物

昆明医科大学第一附属医院消化内科

Summary

Changes in plasma and fecal metabolomes in colorectal cancer (CRC) progression (normal-adenoma-CRC) remain unclear. Here, plasma and fecal samples were collected from four independent cohorts of 1,251 individuals (422 CRC, 399 colorectal adenoma [CRA], and 430 normal controls [NC]). By metabolomic profiling, signature plasma and fecal metabolites with consistent shift across NC, CRA, and CRC are identified, including CRC-enriched oleic acid and CRC-depleted allocholic acid. Oleic acid exhibits pro-tumorigenic effects in CRC cells, patient-derived organoids, and two murine CRC models, whereas allocholic acid has opposing effects. By integrative analysis, we found that oleic acid or allocholic acid directly binds to α-enolase or farnesoid X receptor-1 in CRC cells, respectively, to modulate cancer-associated pathways. Clinically, we establish a panel of 17 plasma metabolites that accurately diagnoses CRC in a discovery and three validation cohorts (AUC = 0.848–0.987). Overall, we characterize metabolite signatures, mechanistic significance, and diagnostic potential of plasma and fecal metabolomes in CRC.

摘要

结肠直肠癌(CRC)进展(正常-腺瘤-CRC)中血浆和粪便代谢组的变化尚不清楚。本研究从四个独立队列的1251名个体中收集血浆和粪便样本 (422例结直肠癌，399例结直肠腺瘤[CRA]，430例正常对照[NC])。通过代谢组学分析，确定了在NC、CRA和CRC之间具有一致变化的标志性血浆和粪便代谢物特征，包括在主要出现在CRC患者中的油酸和不在CRC患者中出现的别胆酸。油酸在CRC细胞、患者来源的类器官和两种鼠CRC模型中表现出促瘤作用，而别胆酸则具有相反的作用。通过综合分析，本研究发现油酸和别胆酸分别直接与CRC细胞中的α-烯醇化酶或法尼酯X受体-1结合，以调节与癌症相关的信号通路。在临床应用方面，本研究建立了一个包含17种血浆代谢物的检测组，该组在发现队列和三个验证队列中均能准确诊断CRC（曲线下面积AUC为0.848-0.987）。总体而言，本研究揭示了CRC血浆和粪便代谢组的代谢特征、潜在机制及其在诊断中的潜在应用价值。

5、Longitudinal on-treatment circulating tumor DNA as a biomarker for real-time dynamic risk monitoring in cancer patients: The EP-SEASON study

纵向治疗循环肿瘤DNA作为癌症患者实时动态风险监测的生物标志物:EP-SEASON研究

中山大学肿瘤防治中心

Summary

Recurrence risks of cancer patient can change during treatment as a result of treatment-related tumor evolution. However, biomarkers that can monitor these changes are lacking. Here, we investigated whether tracking circulating tumor DNA (ctDNA) dynamics through liquid biopsy can inform real-time recurrence risk. Nasopharyngeal carcinoma (NPC) provides an ideal model where cell-free Epstein-Barr virus (EBV) DNA (cfEBV DNA), a ctDNA, can be sensitively detected. We conducted the EP-SEASON study (NCT03855020) and prospectively recruited 1,000 NPC patients undergoing per-protocol cfEBV DNA assessments at 11 time points and receiving sequential chemo-radiotherapy. Longitudinal cfEBV DNA displayed distinct patterns during neoadjuvant chemotherapy and radiotherapy. Despite the prognostic significance of cfEBV DNA at each time point, real-time recurrence risks changed in sync with cfEBV DNA dynamics. Furthermore, we identified phenotypes of whole-course ctDNA changing dynamics associated with different survival outcomes. In conclusion, tracking longitudinal on-treatment ctDNA can forecast real-time recurrence risk, facilitating risk-adapted, individualized patient management.

摘要

癌症患者在治疗过程中的复发风险可能因治疗引起的肿瘤演变而发生改变。然而，目前缺乏能够监测这些变化的生物标志物。本研究旨在探讨通过液体活检追踪循环肿瘤DNA（ctDNA）的动态变化，是否能够为实时评估复发风险提供信息。鼻咽癌（NPC）提供了一个理想的模型，患者循环中的EBV DNA（cfEBV DNA）作为一种ctDNA，能够被灵敏地检测。本研究开展了EP-SEASON研究（NCT03855020），并前瞻性地纳入了1000名NPC患者，这些患者在11个时间点接受了按方案cfEBV DNA检测，并接受了序贯的放化疗。结果显示，在辅助化疗和放疗期间，cfEBV DNA的纵向变化呈现出特定的模式。尽管cfEBV DNA在每个时间点的预后价值显著，但其动态变化与实时复发风险的变化保持一致。此外，本研究还识别出与不同生存结局相关的一系列全疗程ctDNA动态变化表型。综上所述，对治疗期间纵向ctDNA的追踪能够预测实时复发风险，从而有助于实现风险适应性、个体化的患者管理策略。

6、Lymphatic-localized Treg-mregDC crosstalk limits antigen trafficking and restrains anti-tumor immunity

淋巴定位的Treg-mregDC串扰限制抗原运输并抑制抗肿瘤免疫

厦门大学医学与生命科学学院

Summary

The tumor microenvironment (TME) has a significant impact on tumor growth and immunotherapy efficacies. However, the precise cellular interactions and spatial organizations within the TME that drive these effects remain elusive. Using advanced multiplex imaging techniques, we have discovered that regulatory T cells (Tregs) accumulate around lymphatic vessels in the peripheral tumor stroma. This localized accumulation is facilitated by mature dendritic cells enriched in immunoregulatory molecules (mregDCs), which promote chemotaxis of Tregs, establishing a peri-lymphatic Treg-mregDC niche. Within this niche, mregDCs facilitate Treg activation, which in turn restrains the trafficking of tumor antigens to the draining mesenteric lymph nodes, thereby impeding the initiation of anti-tumor adaptive immune responses. Disrupting Treg recruitment to mregDCs inhibits tumor progression. Our study provides valuable insights into the organization of TME and how local crosstalk between lymphoid and myeloid cells suppresses anti-tumor immune responses.

摘要

肿瘤微环境(TME)对肿瘤生长和免疫治疗效果具有显著影响。然而，驱动这些效应的TME内精确的细胞相互作用和空间组织仍然难以捉摸。使用先进的多重成像技术，本研究发现调节性T细胞(Tregs)在肿瘤间质的淋巴管周围聚集。富含免疫调节分子的成熟树突细胞(mregDC)促进了这种局部聚集，这些分子促进Treg的趋化性，从而形成了淋巴周围Treg-mregDC生态位。在这个生态位中，mregDCs促进Treg激活，反过来抑制肿瘤抗原向引流的肠系膜淋巴结的转运，从而阻碍抗肿瘤适应性免疫反应的启动。干扰Treg向mregDCs的募集可抑制肿瘤进展。本研究为TME的组织以及淋巴细胞和髓细胞之间的局部干扰如何抑制抗肿瘤免疫反应提供了有价值的见解。

7、Thyroid hormone suppresses medulloblastoma progression through promoting terminal differentiation of tumor cells

甲状腺激素通过促进肿瘤细胞的终末分化抑制髓母细胞瘤的进展

美国天普大学福克斯蔡斯癌症中心

Summary

Hypothyroidism is commonly detected in patients with medulloblastoma (MB). However, whether thyroid hormone (TH) contributes to MB pathogenicity remains undetermined. Here, we find that TH plays a critical role in promoting tumor cell differentiation. Reduction in TH levels frees the TH receptor, TRα1, to bind to EZH2 and repress expression of NeuroD1, a transcription factor that drives tumor cell differentiation. Increased TH reverses EZH2-mediated repression of NeuroD1 by abrogating the binding of EZH2 and TRα1, thereby stimulating tumor cell differentiation and reducing MB growth. Importantly, TH-induced differentiation of tumor cells is not restricted by the molecular subgroup of MB, suggesting that TH can be used to broadly treat MB subgroups. These findings establish an unprecedented association between TH signaling and MB pathogenicity, providing solid evidence for TH as a promising modality for MB treatment.

摘要

髓母细胞瘤(MB)患者常见甲状腺功能减退。然而，甲状腺激素(TH)是否有助于MB的致病性仍未确定。本研究发现TH在促进肿瘤细胞分化中起着关键作用。TH水平的降低释放了TH受体TRα1，使其与EZH2结合并抑制NeuroD1的表达，NeuroD1是一种驱动肿瘤细胞分化的转录因子。TH的增加通过取消EZH2和TRα1的结合逆转EZH2介导的对NeuroD1的抑制，从而刺激肿瘤细胞分化和抑制MB生长。重要的是，TH诱导的肿瘤细胞分化不受MB分子亚群的限制，这表明TH可以广泛用于治疗MB亚群。这些发现建立了TH信号和MB致病性之间前所未有的联系，为TH作为MB治疗的潜在方法提供了坚实的基础。

8、Interleukin-21 engineering enhances NK cell activity against glioblastoma via CEBPD

白细胞介素-21工程通过CEBPD增强NK细胞抗胶质母细胞瘤活性

美国德克萨斯大学安德森癌症中心

Summary

Glioblastoma (GBM) is an aggressive brain cancer with limited therapeutic options. Natural killer (NK) cells are innate immune cells with strong anti-tumor activity and may offer a promising treatment strategy for GBM. We compared the anti-GBM activity of NK cells engineered to express interleukin (IL)-15 or IL-21. Using multiple in vivo models, IL-21 NK cells were superior to IL-15 NK cells both in terms of safety and long-term anti-tumor activity, with locoregionally administered IL-15 NK cells proving toxic and ineffective at tumor control. IL-21 NK cells displayed a unique chromatin accessibility signature, with CCAAT/enhancer-binding proteins (C/EBP), especially CEBPD, serving as key transcription factors regulating their enhanced function. Deletion of CEBPD resulted in loss of IL-21 NK cell potency while its overexpression increased NK cell long-term cytotoxicity and metabolic fitness. These results suggest that IL-21, through C/EBP transcription factors, drives epigenetic reprogramming of NK cells, enhancing their anti-tumor efficacy against GBM.

摘要

胶质母细胞瘤(GBM)是一种侵袭性脑癌，治疗方法有限。自然杀伤（NK）细胞作为先天免疫细胞，具备显著的抗肿瘤活性，并可能成为GBM治疗策略的新希望。本研究对比了两种工程化NK细胞，一种表达IL-15，另一种表达IL-21，并评估了二者对GBM的抗肿瘤活性。通过多种体内模型实验，本研究发现IL-21 NK细胞在安全性和长期抗肿瘤效果上均优于IL-15 NK细胞。特别是，局部注射IL-15 NK细胞显示出毒性且无法有效控制肿瘤。IL-21 NK细胞展现出独特的染色质可及性特征，其中CCAAT/增强子结合蛋白（C/EBP）家族成员，尤其是CEBPD，扮演着关键角色，调节其功能增强。CEBPD的缺失导致IL-21 NK细胞功效的丧失，而其过表达则增强了NK细胞的长期细胞毒性和代谢适应性。这些发现表明，IL-21通过C/EBP转录因子介导，驱动NK细胞的表观遗传重编程，从而显著提升了其针对GBM的抗肿瘤效能。

Sep 09, 2024，Volume 42，Issue 9，p1473-1630

2024年9月，Cancer Cell共发表15篇文章，其中包括Letter 1篇；Commentaries 2篇；Previews 3篇；Perspective 1篇；Articles 7篇；Corrections 1篇。

1、Glioblastoma induces the recruitment and differentiation of dendritic-like “hybrid” neutrophils from skull bone marrow

胶质母细胞瘤诱导颅骨骨髓树突样“混合”中性粒细胞的募集和分化

美国加州大学旧金山分校神经外科

Summary

Tumor-associated neutrophil (TAN) effects on glioblastoma (GBM) biology remain under-characterized. We show here that neutrophils with dendritic features—including morphological complexity, expression of antigen presentation genes, and the ability to process exogenous peptide and stimulate major histocompatibility complex (MHC)II-dependent T cell activation—accumulate intratumorally and suppress tumor growth in vivo. Trajectory analysis of patient TAN scRNA-seq identifies this “hybrid” dendritic-neutrophil phenotype as a polarization state that is distinct from canonical cytotoxic TANs, and which differentiates from local precursors. These hybrid-inducible immature neutrophils—which we identified in patient and murine glioblastomas—arise not from circulation, but from local skull marrow. Through labeled skull flap transplantation and targeted ablation, we characterize calvarial marrow as a contributor of antitumoral myeloid antigen-presenting cells (APCs), including TANs, which elicit T cell cytotoxicity and memory. As such, agents augmenting neutrophil egress from skull marrow—such as intracalvarial AMD3100, whose survival-prolonging effect in GBM we report—present therapeutic potential.

摘要

肿瘤相关的中性粒细胞(TAN)对胶质母细胞瘤(GBM)生物学的影响仍不明确。本研究表明，具有树突状特征的中性粒细胞—包括形态复杂性、抗原呈递基因的表达以及处理外源肽和刺激MHCII依赖性T细胞活化的能力—在肿瘤内部积累，并在体内抑制肿瘤生长。通过对患者TAN的单细胞RNA测序轨迹分析，鉴定出这种“混合型”的树突样中性粒细胞表型是一种独特的极化状态，与典型的细胞毒性TANs不同，且与局部祖细胞有所区分。这些在患者和鼠类GBM中发现的混合型诱导的未成熟中性粒细胞并非来源于血液循环，而是起源于局部颅骨骨髓。通过颅骨瓣移植和靶向消融技术，本研究证实颅骨骨髓是产生抗肿瘤性髓系抗原呈递细胞（APC）的重要来源，包括TANs，它们能够引发T细胞的细胞毒性和记忆反应。因此，能够促进中性粒细胞从颅骨骨髓中逸出的药物，如本研究报道的能够延长GBM患者生存期的颅骨内AMD3100，显示出潜在的治疗价值。

2、GABAergic neuronal lineage development determines clinically actionable targets in diffuse hemispheric glioma, H3G34-mutant

GABA能神经元谱系发育决定弥漫性半球胶质瘤（H3G34 突变型）的临床可操作靶点

丹娜法伯 /波士顿儿童癌症和血液疾病中心

Summary

Diffuse hemispheric gliomas, H3G34R/V-mutant (DHG-H3G34), are lethal brain tumors lacking targeted therapies. They originate from interneuronal precursors; however, leveraging this origin for therapeutic insights remains unexplored. Here, we delineate a cellular hierarchy along the interneuron lineage development continuum, revealing that DHG-H3G34 mirror spatial patterns of progenitor streams surrounding interneuron nests, as seen during human brain development. Integrating these findings with genome-wide CRISPR-Cas9 screens identifies genes upregulated in interneuron lineage progenitors as major dependencies. Among these, CDK6 emerges as a targetable vulnerability: DHG-H3G34 tumor cells show enhanced sensitivity to CDK4/6 inhibitors and a CDK6-specific degrader, promoting a shift toward more mature interneuron-like states, reducing tumor growth, and prolonging xenograft survival. Notably, a patient with progressive DHG-H3G34 treated with a CDK4/6 inhibitor achieved 17 months of stable disease. This study underscores interneuronal progenitor-like states, organized in characteristic niches, as a distinct vulnerability in DHG-H3G34, highlighting CDK6 as a promising clinically actionable target.

摘要

弥漫性半球胶质瘤（DHG-H3G34R/V突变型，DHG-H3G34）是一种缺乏靶向治疗方案的致命性脑肿瘤。它们起源于中间神经元的前体细胞，然而，利用这一起源来获得治疗见解的研究尚未展开。本研究详细描绘了中间神经元谱系发育过程中连续的细胞层次结构，并发现DHG-H3G34肿瘤的细胞排列模式与人类大脑发育期间围绕中间神经元巢的祖细胞流的空间模式相呼应。将本研究的发现与全基因组CRISPR-Cas9筛选结果相结合，将在中间神经元谱系祖细胞中上调的基因鉴定为关键依赖因子。在这些基因中，CDK6被鉴定为一个可靶向的潜在治疗靶点：DHG-H3G34肿瘤细胞对CDK4/6抑制剂以及CDK6特异性降解剂表现出增强的敏感性，这促进了细胞向更成熟的中间神经元状态转变，从而抑制肿瘤生长并延长异种移植模型的生存期。值得注意的是，接受CDK4/6抑制剂治疗的进行性DHG-H3G34患者实现了17个月的疾病稳定。本研究强调了在特征性生态位中组织的中间神经元祖细胞样状态，是DHG-H3G34的一个独特治疗靶点，突出了CDK6作为临床干预的潜在重要靶标。

3、Fibrotic response to anti-CSF-1R therapy potentiates glioblastoma recurrence

对抗CSF-1R治疗的纤维化反应会增加胶质母细胞瘤的复发

瑞士洛桑大学肿瘤学系

Summary

Glioblastoma recurrence is currently inevitable despite extensive standard-of-care treatment. In preclinical studies, an alternative strategy of targeting tumor-associated macrophages and microglia through CSF-1R inhibition was previously found to regress established tumors and significantly increase overall survival. However, recurrences developed in ∼50% of mice in long-term studies, which were consistently associated with fibrotic scars. This fibrotic response is observed following multiple anti-glioma therapies in different preclinical models herein and in patient recurrence samples. Multi-omics analyses of the post-treatment tumor microenvironment identified fibrotic areas as pro-tumor survival niches that encapsulated surviving glioma cells, promoted dormancy, and inhibited immune surveillance. The fibrotic treatment response was mediated by perivascular-derived fibroblast-like cells via activation by transforming growth factor β (TGF-β) signaling and neuroinflammation. Concordantly, combinatorial inhibition of these pathways inhibited treatment-associated fibrosis, and significantly improved survival in preclinical trials of anti-colony-stimulating factor-1 receptor (CSF-1R) therapy.

摘要

尽管接受了广泛的标准治疗方案，胶质母细胞瘤的复发目前仍然是不可避免的。在临床前研究中，通过抑制CSF-1R来靶向肿瘤相关巨噬细胞和小胶质细胞的替代策略已被发现可以消退已建立的肿瘤，并显著提高总生存率。然而，在长期研究中，大约50%的小鼠发生了复发，这与纤维化疤痕持续相关。这种纤维化反应在本研究中以及在不同临床前模型和患者复发样本中，在多种抗胶质瘤治疗之后都会观察到。对治疗后肿瘤微环境的多组学分析确定纤维化区域充当了肿瘤生存的有利生态位，其包裹存活的神经胶质瘤细胞，促进休眠，并抑制免疫监视。这种纤维化治疗反应是由血管周围来源的成纤维细胞样细胞通过转化生长因子β (TGF-β)信号和神经炎症的激活而介导的。相应的，联合抑制这些通路能抑制治疗相关的纤维化，并显著提高CSF-1R治疗的临床前试验的存活率。

4、Distinct clinical outcomes and biological features of specific KRAS mutants in human pancreatic cancer

人胰腺癌中特异性KRAS突变体的独特临床结局和生物学特征

美国纪念斯隆-凯特琳癌症中心

Summary

KRAS mutations in pancreatic ductal adenocarcinoma (PDAC) are suggested to vary in oncogenicity but the implications for human patients have not been explored in depth. We examined 1,360 consecutive PDAC patients undergoing surgical resection and find that KRAS^G12R mutations are enriched in early-stage (stage I) disease, owing not to smaller tumor size but increased node-negativity. KRAS^G12R tumors are associated with decreased distant recurrence and improved survival as compared to KRAS^G12D. To understand the biological underpinnings, we performed spatial profiling of 20 patients and bulk RNA-sequencing of 100 tumors, finding enhanced oncogenic signaling and epithelial-mesenchymal transition (EMT) in KRAS^G12D and increased nuclear factor κB (NF-κB) signaling in KRAS^G12R tumors. Orthogonal studies of mouse Kras^G12R PDAC organoids show decreased migration and improved survival in orthotopic models. KRAS alterations in PDAC are thus associated with distinct presentation, clinical outcomes, and biological behavior, highlighting the prognostic value of mutational analysis and the importance of articulating mutation-specific PDAC biology.

摘要

胰腺导管腺癌(PDAC)中的KRAS突变被认为具有不同的致癌性，但对人类患者的影响尚未深入研究。本研究检查了1360名接受手术切除的PDAC患者，发现KRAS^G12R突变在早期(I期)疾病患者中更常见，这不是因为肿瘤体积更小，而是因为淋巴结阴性率增加。与KRAS^G12D相比，KRAS^G12R肿瘤与减少远处复发和提高存活率相关。为了理解其生物学基础，本研究对20名患者进行了空间分析，并对100例肿瘤进行了大量RNA测序，发现KRAS^G12D的致癌信号和上皮-间质转化(EMT)增强，KRAS^G12R肿瘤的核因子κB (NF-κB)信号增强。小鼠Kras^G12R PDAC类器官的正交研究显示在原位模型中迁移减少且存活率提高。因此，PDAC的KRAS变异与不同的临床表现、临床结果和生物学行为相关，突出了突变分析的预后价值和阐明突变特异性PDAC生物学的重要性。

5、Circulating tumor DNA-based stratification strategy for chemotherapy plus PD-1 inhibitor in advanced non-small-cell lung cancer

基于循环肿瘤DNA的晚期非小细胞肺癌化疗联合PD-1抑制剂分层策略

中国协和医科大学肿瘤医院

Summary

Stratification strategies for chemotherapy plus PD-1 inhibitors in advanced non-small-cell lung cancer (NSCLC) are critically demanded. We performed high-throughput panel-based deep next-generation sequencing and low-pass whole genome sequencing on prospectively collected circulating tumor DNA (ctDNA) specimens from 460 patients in the phase 3 CHOICE-01 study at different time points. We identified predictive markers for chemotherapy plus PD-1 inhibitor, including ctDNA status and genomic features such as blood-based tumor mutational burden, intratumor heterogeneity, and chromosomal instability. Furthermore, we established an integrated ctDNA-based stratification strategy, blood-based genomic immune subtypes (bGIS) scheme, to distinguish patients who benefit from the addition of PD-1 inhibitor to first-line chemotherapy. Moreover, we demonstrated potential applications for the dynamic monitoring of ctDNA. Overall, we proposed a potential therapeutic algorithm based on the ctDNA-based stratification strategy, shedding light on the individualized management of immune-chemotherapies for patients with advanced NSCLC.

摘要

在晚期非小细胞肺癌（NSCLC）中，化疗联合PD-1抑制剂的治疗分层策略至关重要。本研究对来自460名患者（在CHOICE-01研究的第3期中，收集了不同时间点的循环肿瘤DNA（ctDNA）样本）进行了高通量二代测序和低通量全基因组测序，确定了化疗联合PD-1抑制剂的预测标志物，包括ctDNA状态和基因组特征，如基于血液的肿瘤突变负荷、肿瘤内异质性和染色体不稳定性。此外，本研究建立了一个基于ctDNA的综合分层策略，即基于血液的基因组免疫亚型(bGIS)方案，以区分受益于一线化疗联合PD-1抑制剂的患者。此外，本研究展示了动态监测ctDNA的潜在应用。总之，本研究提出了一种基于ctDNA的分层策略的潜在治疗算法，为晚期非小细胞肺癌患者免疫化疗的个体化管理提供了思路。

6、Effect of neoadjuvant chemoradiotherapy with or without PD-1 antibody sintilimab in pMMR locally advanced rectal cancer: A randomized clinical trial

新辅助放化疗与PD-1抗体联合与否对pMMR局部晚期直肠癌的疗效:一项随机临床试验

中山大学肿瘤防治中心放射肿瘤科

Summary

Neoadjuvant chemoradiotherapy (NACRT) was the standard treatment for patients with locally advanced rectal cancer (LARC) with proficient mismatch repair (pMMR) proteins. In this randomized phase 2 trial (ClinicalTrial.gov: NCT04304209), 134 pMMR LARC patients were randomly (1:1) assigned to receive NACRT or NACRT and the programmed cell death protein 1 (PD-1) antibody sintilimab. As the primary endpoint, the total complete response (CR) rate is 26.9% (18/67, 95% confidence interval [CI] 16.0%–37.8%) and 44.8% (30/67, 95% CI 32.6%–57.0%) in the control and experimental arm, respectively, with significant difference (p = 0.031 for chi-squared test). Response ratio is 1.667 (95% CI 1.035–2.683). Immunohistochemistry shows PD-1 ligand 1 (PD-L1) combined positive score is associated with the synergistic effect. The safety profile is similar between the arms. Adding the PD-1 antibody sintilimab to NACRT significantly increases the CR rate in pMMR LARC, with a manageable safety profile. PD-L1 positivity may help identify patients who might benefit most from the combination therapy.

摘要

新辅助放化疗(NACRT)是具有熟练错配修复(pMMR)蛋白的局部晚期直肠癌(LARC)患者的标准治疗。在这项2期随机临床试验(ClinicalTrial.gov: NCT04304209)中，134名pMMR LARC患者被随机(1:1)分配接受NACRT或NACRT联合程序性细胞死亡蛋白1 (PD-1)抗体sintilimab治疗。作为主要终点，对照组和实验组的总完全缓解率(CR)分别为26.9% (18/67，95%可信区间[CI]16.0%-37.8%)和44.8% (30/67，95% CI 32.6%-57.0%)，两组之间存在显著差异(卡方检验p = 0.031)。反应比率为1.667 (95% CI 1.035–2.683)。免疫组织化学显示PD-1配体1 (PD-L1)结合阳性分数与协同效应相关。两组的安全状况相似。在NACRT中加入PD-1抗体sintilimab可显著增加pMMR LARC的CR率，且安全性可控。PD-L1阳性可能有助于确定从联合治疗中获益最大的患者。

7、Combination anti-PD-1 and anti-CTLA-4 therapy generates waves of clonal responses that include progenitor-exhausted CD8+ T cells

抗PD-1和抗CTLA-4联合治疗诱导包括祖细胞耗竭的CD8+ T细胞的多轮细胞克隆反应

美国宾夕法尼亚大学佩雷尔曼医学院

Summary

Combination checkpoint blockade with anti-PD-1 and anti-CTLA-4 antibodies has shown promising efficacy in melanoma. However, the underlying mechanism in humans remains unclear. Here, we perform paired single-cell RNA and T cell receptor (TCR) sequencing across time in 36 patients with stage IV melanoma treated with anti-PD-1, anti-CTLA-4, or combination therapy. We develop the algorithm Cyclone to track temporal clonal dynamics and underlying cell states. Checkpoint blockade induces waves of clonal T cell responses that peak at distinct time points. Combination therapy results in greater magnitude of clonal responses at 6 and 9 weeks compared to single-agent therapies, including melanoma-specific CD8+ T cells and exhausted CD8+ T cell (TEX) clones. Focused analyses of TEX identify that anti-CTLA-4 induces robust expansion and proliferation of progenitor TEX, which synergizes with anti-PD-1 to reinvigorate TEX during combination therapy. These next generation immune profiling approaches can guide the selection of drugs, schedule, and dosing for novel combination strategies.

摘要

联合应用抗PD-1和抗CTLA-4抗体在黑色素瘤治疗中展现出显著的疗效潜力。然而，其在人体内的作用机制尚未完全阐明。本研究对36名接受抗PD-1、抗CTLA-4或其联合治疗的IV期黑色素瘤患者进行了时间序列的单细胞RNA测序和T细胞受体（TCR）测序。通过开发Cyclone算法追踪时间序列的克隆动态和潜在的细胞状态。免疫检查点阻断引发了克隆性T细胞反应波，在不同的时间点达到峰值。与单药治疗相比，联合治疗在第6周和第9周产生更大量的克隆反应，包括黑色素瘤特异性CD8+ T细胞和耗竭CD8+ T细胞(TEX)克隆。对TEX的深入分析确定，抗CTLA-4诱导祖TEX的强烈扩增和增殖，其与抗PD-1协同以在联合治疗期间重新激活TEX。这些先进的免疫组学方法有望指导新型联合治疗策略的药物选择、治疗时机和剂量调整。

汇报人：周菁

导师：刘世喜

审核：李俊虹、任建君