Cancer Communications最新文献_第7页

Cover Image, Volume 44, Issue 4 封面图片，第 44 卷第 4 期

IF 16.2 1区医学 Q1 ONCOLOGY

Cancer Communications

Pub Date : 2024-04-18 DOI: 10.1002/cac2.12544

Xuechun Wang, Anna Juncker-Jensen, Gang Huang, Mate Levente Nagy, Xuemin Lu, Liang Cheng, Xin Lu

The cover image is based on the Correspondence Spatial relationship of tertiary lymphoid structures and tumor-associated neutrophils in bladder cancer and prognostic potential for anti-PD-L1 immunotherapy by Xuechun Wang et al., https://doi.org/10.1002/cac2.12491.

封面图像基于 Xuechun Wang 等人的 Correspondence Spatial relationship of tertiary lymphoid structures and tumor-associated neutrophils in bladder cancer and prognostic potential for anti-PD-L1 immunotherapy，https://doi.org/10.1002/cac2.12491。

引用次数: 0

Dietary long-chain fatty acid metabolism boosts antitumor immune response 膳食长链脂肪酸代谢可增强抗肿瘤免疫反应。

IF 16.2 1区医学 Q1 ONCOLOGY

Cancer Communications

Pub Date : 2024-04-12 DOI: 10.1002/cac2.12543

Jiaming Wang, Xuetao Cao

Overcoming resistance to immune checkpoint blockade (ICB) therapy will pave the way for effective ICB cancer immunotherapy since a large proportion of cancer patients are not responsive to ICB immunotherapy [1]. The molecular mechanisms of ICB resistance are diverse, including tumor-intrinsic resistant factors (such as genetic and epigenetic disorders), immunosuppressive/disabled factors (such as T cell exhaustion), and environmental restrictive factors (such as neuroendocrine stress and metabolic reprogramming). Deciphering the mechanisms for ICB resistance will provide immense potential for designing new immunotherapeutic strategies in refractory cancers. The tumor microenvironment (TME) includes diverse types of cells, such as immune cells, cancer-associated fibroblasts, and endothelial cells, as well as intercellular cytokines/chemokines, growth factors, and metabolites, which have been recognized as crucial determinants in ICB responsiveness. The recent advent of high-throughput metabolomics and lipidomics analysis reveals that metabolic reprogramming in TME is closely associated with cancer cell invasion, regulated cell death, immune escape, and chemoresistance [2]. On the other hand, immunometabolism also modulates tumor-associated immune cell function and immunotherapy efficacy. For instance, higher expression of major facilitator superfamily domain containing 2A (MFSD2A) in gastric cancer cells inhibits transforming growth factor beta 1 (TGF-β1) production by suppressing cyclooxygenase 2 (COX2)-prostaglandin synthesis, thus promoting antitumor immunity via reprogramming TME [3].As a major component of lipids in TME, long-chain fatty acids (LCFAs) are important energy supply and cellular membrane components for cancer cells. Indeed, various types of LCFAs have been found in TME, showing different and sometimes opposite influences on tumor progression and antitumor immunity [4]. For example, palmitic acid promotes metastasis in oral carcinomas and melanoma mouse models through stimulating intratumoral Schwann cells and innervation [5], whereas linoleic acid potentiates CD8+ T cell antitumor functions via enhancing endoplasmic reticulum-mitochondria contact formation and energetics fitness [6]. Therefore, better understanding of the molecular mechanism for each individual LCFA in tumor immunity is meaningful since it may improve cancer immunotherapy through targeting metabolic reprogramming of TME. In a recent study published in Cell Metabolism, Lai et al. [7] found dietary elaidic acid (EA) supplementation elevates tumoral major histocompatibility complex-1 (MHC-I) expression via acyl-coenzyme A synthetase long chain family member 5 (ACSL5), thus suppressing tumor growth and enhancing anti-programmed cell death protein 1 (anti-PD-1) efficacy (Figure 1).Acyl-coenzyme A synthetase long-chain family members (ACS

虽然表达ACSL5的LLC肿瘤中CD8+ T细胞数量增加，但CD4+ T细胞数量和T细胞产生的细胞因子不受影响。因此，作者推测 ACSL5 可能会调节肿瘤对 T 细胞介导的杀伤的敏感性。事实上，他们发现，在体外共培养系统中，ACSL5 的缺乏会使肿瘤细胞对 CD8+ T 细胞介导的细胞毒性更具抵抗力。肿瘤免疫原性不足是导致 ICB 抗性的关键原因，因为 CTL 通过 T 细胞受体（TCR）识别 MHC-I 分子呈递的肿瘤抗原来介导肿瘤细胞杀伤 [9]。因此，作者发现 ACSL5 缺失的肿瘤细胞中 MHC-I 表达下调。通过对野生型和 ACSL5 基因缺陷型细胞进行转录组分析，作者注意到，ACSL5 基因敲除后，MHC-I 的关键转录激活因子之一 NLR 家族含 CARD 结构域 5（NLRC5）的表达减少。沉默 NLRC5 可完全消除 ACSL5 异位表达对 MHC-I 的上调，这表明 ACSL5-NLRC5-MHC-I 轴决定了肿瘤细胞的免疫原性，从而诱导抗肿瘤免疫。根据各种 LCFAs 的筛选，作者发现油酸反式异构体 EA（动物脂肪和植物油的常见成分）能有效增强基础和 IFNγ 刺激的 MHC-I 表达。ACSL5或NLRC5缺乏会影响EA对MHC-I的诱导，这进一步验证了EA-ACSL5-NLRC5-MHC-I轴在抗肿瘤免疫代谢调节中的作用。此外，腹腔注射和胃内注射EA都能以免疫依赖的方式抑制体内B16-F10肿瘤的生长。同样，EA与抗PD-1疗法联合使用可显著减少LLC肿瘤负荷，而LLC原本对ICB具有抗药性，这突显了膳食补充EA在促进对ICB的反应性方面具有良好的治疗潜力。最后，作者发现血浆EA水平越高，患者对ICB的反应越好，无进展生存期也越长，这意味着血浆EA可能是ICB疗效的理想预测指标。尽管大量研究表明反式脂肪酸（TFAs）有害，尤其是对心血管疾病有害，但这项研究揭示了反式脂肪酸在增强肿瘤免疫原性和提高抗肿瘤免疫反应方面的意想不到的作用。然而，仍有许多问题需要解决。代谢酶ACSL5如何调控核转录因子NLRC5的表达，以及NLRC5如何作为脂肪酸代谢改变的传感器，这些问题都不清楚。与这一发现相反，有报道称 EA 可通过激活 Wnt 和细胞外信号调节激酶（ERK）信号来促进小鼠结直肠癌细胞的生长和转移[10]。EA在不同肿瘤模型中的相反功能是否是由于TME的异质性造成的，还需要进一步研究。尽管作者关注的是 EA 对肿瘤细胞的抗肿瘤作用，但 EA 是否也直接影响 CD8+ T 细胞的功能尚不清楚。研究摄入 EA 期间免疫细胞的脂质代谢重构、脂肪酸介导的信号转导和抗肿瘤功能调控也很有意义。作者利用同型标记技术证明了 ACSL5 能将 EA 转化为 EA-CoA，然而，EA-CoA 是否直接通过调控靶蛋白酰化（如棕榈酰化）来刺激 MHC-I 的表达仍是未知数。转化为 EA-CoA 后，活化的脂肪酸是下游脂质代谢途径（如脂肪酸 β-氧化（FAO）、脂质生物合成和蛋白质酰化）所必需的（图 1）。我们未发表的数据表明，ACSL5 可调控磷脂合成和细胞膜特性，这也可能影响肿瘤细胞中 MHC-1 和免疫细胞中其他受体的膜转位。虽然作者在本文[7]中排除了FAO对ACSL5介导的MHC-I表达的影响，但ACSL5的代谢扰动仍然复杂，值得进一步探讨EA-ACSL5轴在肿瘤免疫学中的深层分子机制。曹雪涛指导并修改了手稿。作者声明他们没有利益冲突。

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引用次数: 0

Proteomics of cell-free breast cancer scaffolds identify clinically relevant imprinted proteins and cancer-progressing properties 无细胞乳腺癌支架的蛋白质组学鉴定临床相关的印迹蛋白和癌症进展特性

IF 20.1 1区医学 Q1 ONCOLOGY

Cancer Communications

Pub Date : 2024-04-04 DOI: 10.1002/cac2.12542

Anna Gustafsson, Emma Jonasson, Anders Ståhlberg, Göran Landberg

The composition of the extracellular tumor microenvironment (TME) has not been fully delineated, limiting the understanding of general cancer-progressing properties within the cancer niche. The interplay and dynamics between cancer cells and the surrounding structures and cells clearly differ between various subtypes of cancer, adding to the complexity of precision medicine [1].To better understand the composition and to define the imprinted proteins of the TME in breast cancer and its potential associations with clinical properties of the disease, we performed global proteomic analysis on a cohort of 63 decellularized patient-derived scaffolds (PDSs). PDSs represents the cell-free TME and were prepared using primary lesions from breast cancer patients with available clinicopathological data (Figure 1A, Supplementary file of methods). The PDS method has earlier been shown to maintain tumor tissue heterogeniety in vitro, producing quantitative assessments of the activity of the TME when studying cancer cell lines adapted to various PDS-based cell cultures [2]. Specific gene changes in the cancer population induced by the heterogenous PDS culture conditions have also been linked to clinical observations, validating the selected strategy for this study [2-5].The analysis of the cell-free PDSs identified 1,844 unique proteins (Supplementary Table S1), showing enrichment for proteins related to metabolism, translation, transport, immunity, and extracellular matrix (ECM). Surprisingly, most proteins were annotated as cytoplasmic, suggesting that intracellular proteins were also associated with the PDSs, as further deliberated below (Supplementary Figure S1). When comparing the protein contents from primary cancer samples with adjacent normal breast tissues, 1,280 of the 1,844 detected proteins from the cell-free compartments were differentially expressed. Normal breast tissues were, in comparison to the PDSs, enriched for proteins involved in oxidation-reducing processes, secretion, regulation of exocytosis, and ECM organization (Supplementary Figure S2).Next, we used k-means clustering to identify potential subgroups of patients based on the protein composition of the cell-free PDSs. PDS Clusters 1-3 were recognized, distinguished by the expression of proteins in Clusters A-C. Interestingly, the PDS clusters were significantly associated with cancer subtypes (Figure 1B and Supplementary Table S2). Cluster 1 was mainly derived from lobular cancers (63%) and low-grade cancers, showing high levels of 458 proteins involved in ECM organization, biological adhesion, and leukocyte-mediated immunity forming protein Cluster A. Cluster 2 was primarily derived from ductal cancers (77%) and showed pronounced expression of protein Cluster B, comprising of 396 proteins related to exocytosis, secretion and neutrophil degranulation. Cluster 3 included a mixture of ductal and lobular cancers with the highe

接下来，我们根据无细胞 PDS 的蛋白质组成，使用 k-means 聚类方法来识别潜在的患者亚群。根据簇 A-C 中蛋白质的表达情况，我们识别出了 PDS 簇 1-3。有趣的是，PDS 群与癌症亚型显著相关（图 1B 和补充表 S2）。簇 1 主要来自小叶癌（63%）和低级别癌症，显示出高水平的 458 种蛋白质，这些蛋白质涉及 ECM 组织、生物粘附和白细胞介导的免疫，形成了蛋白质簇 A。第 3 组包括导管癌和小叶癌的混合体，其中 C 组蛋白质含量最高，含有 990 个主要参与代谢过程和建立细胞定位的蛋白质。在独立于已定义的簇鉴定两种癌症类型的蛋白质时（图 1C 和补充表 S3），导管癌富含被归类为修饰酶、代谢物相互转换酶、RNA 代谢蛋白和翻译蛋白的蛋白质。与此相反，小叶癌的 ECM 蛋白和防御/免疫蛋白含量较高（图 1D），这支持了早先的研究结果，即小叶癌亚群可能对免疫靶向癌症疗法更敏感[1]。与进展性疾病和复发相关的 52 个蛋白质主要分为转运体和代谢物相互转换酶，而与非复发性癌症相关的 31 个蛋白质主要是细胞骨架和支架/适配蛋白。有趣的是，在与侵袭性疾病相关的蛋白质中，角蛋白和溶质载体（SLC）家族的成员非常突出，在14种已鉴定的角蛋白中，有8种在后来疾病复发患者的PDS中含量更高（图1F）。在单变量分析（图 1G）和多变量分析（危险比 = 14.86，P = 0.01）中，PDSs 中较高水平的 KRT78 与较差的无病生存率显著相关。为了进一步确定乳腺癌中的支架内容，我们根据传统上具有 TME 代表性的 126 个 ECM 相关蛋白子集对 PDSs 进行了聚类（图 1H 和补充表 S4）。观察到三个新的基于 ECM 的 PDS 聚类，它们与之前报告的聚类只有部分重叠（补充图 S3），并与癌症分级和患者年龄有显著关联（补充表 S5-S6）。ECM-1群组显示低级别癌症比例高，患者年龄参差不齐，其特征是胶原、微纤相关蛋白（EMILIN1、MFAP2）、纤连蛋白（FBN1、FBN2）、潜伏转化生长因子β结合蛋白LTBP1和过氧化物酶PRDX4含量高，以及整合素亚基ITGB2含量低。群组 ECM-2 与高级别癌症、患者年龄较大有关，并与较低水平的 ECM 蛋白（尤其是胶原和层粘连蛋白亚基）以及结构蛋白 tenascin XB (TNXB) 紧密相关。相比之下，ECM-3 组主要包括各年龄段的低级别癌症，ECM 蛋白含量较高。当详细研究 PDS 中胶原蛋白的丰度与患者年龄的关系时，在 21 种检测到的胶原蛋白中，有 10 种随着患者年龄的增加而明显逐渐减少（图 1I）。重要的是，所提供的数据表明，在恶性程度较低的低级别 TME 中，与 ECM 相关的蛋白质通常更为丰富。这表明，模仿侵袭性乳腺癌的三维生长模型不能仅使用 ECM 蛋白进行再现，还应该辅以癌症龛位中存在的其他蛋白。癌症患者的年龄也与 PDS 的 ECM 组成有关，年轻患者表现出更高水平的 ECM 蛋白，特别是胶原蛋白。胶原蛋白的更替是组织稳态的正常组成部分，而在包括皮肤在内的老年组织中，胶原蛋白通常会变得更加疏松、杂乱和破碎[7]。老年患者的药代动力学特征也与年轻患者不同。

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引用次数: 0

Discovering genetic biomarkers for targeted cancer therapeutics with eXplainable Artificial Intelligence 利用 eXplainable 人工智能发现癌症靶向治疗的基因生物标志物

IF 16.2 1区医学 Q1 ONCOLOGY

Cancer Communications

Pub Date : 2024-04-02 DOI: 10.1002/cac2.12530

Debaditya Chakraborty, Elizabeth Gutierrez-Chakraborty, Cristian Rodriguez-Aguayo, Hakan Başağaoğlu, Gabriel Lopez-Berestein, Paola Amero

High-Grade Serous Ovarian Cancer (HGSC) is the most prevalent and lethal form of gynecologic malignancies [1], accounting for 70%-80% of ovarian cancer fatalities. Despite decades of research, the overall survival rate for HGSC has remained largely unchanged [2], and patients with advanced stages of the disease have only a 41% chance of surviving beyond five years [3]. Investigating the genomic and immune profiles of long-term HGSC survivors could offer valuable insights into the underlying tumor biology and inform potential therapeutic strategies [4]. This study advances upon prior research by employing an innovative eXplainable Artificial Intelligence (XAI) integrated with a hypothesis-driven probabilistic methodology to dissect the intricate genetic underpinnings linked to HGSC's survival outcomes in a cohort of 407 patients. The objective of this article was to uncover the most critical prognostic biomarkers from a pool of 655 potential targets through our distinctive data-driven approach and determine the impacts of potentially modulating the identified biomarkers on HGSC outcomes.Recent studies indicate that AI models are often referred to as “black boxes” because their decision-making process lacks transparency [5]. The consensus is that the lack of inherent explainability is problematic as this produces biases, creates difficulties in detecting false positives and negatives, and conceals potential insights that may be derived from AI [6]. In this study, we provide evidence demonstrating how XAI can enhance biological explainability by revealing novel insights from the underlying data (Supplementary Materials and Methods). Our XAI approach distinctively predicts patient outcomes and survival duration based on genetic signatures (predictive AI aspect of the models) and discovers and helps visualize critical biomarkers (biological explainability aspect of the models) in HGSC. To ensure the viability of explanations generated by our XAI, we subsequently validated the most prominent HGSC-promoting biomarker identified by XAI using in vivo murine tumor models (Supplementary Figure S1). The XAI approach outlined in this study is a proof-of-concept that is not only intended to generate high predictive accuracy but also infer the cause-effect relations behind the predictions, identify counterfactuals that are useful for optimizing interventional therapies, and assess the resultant improvements in patients.We report that our models predicted the ≥5-year overall survival probability based on the genetic features of patients (n = 407) with 97.52% accuracy, 100% precision, and 94.74% recall on the testing data that comprised 25% of the total samples that were hidden from the models during the training phase. Insights derived through XAI prioritized the biomarkers that are of utmost importance in determining prognosis for patients with HGSC, which we r

总之，本研究提出了一种开创性的综合方法，将 XAI 和概率方法相结合，以促进对 HGSC 的理解和治疗。我们的研究重点是利用 407 个样本的数据集，破译遗传生物标志物与 HGSC 患者五年生存概率之间复杂的相互作用。XAI 和概率因果关系方法的独特结合不仅证明了预测的高准确性，还提供了有价值的生物学解释，确定了影响患者预后的关键生物标志物。特别是，我们的研究结果强调了 TAF10 和 IL27RA 等生物标志物在影响生存率方面的作用，揭示了它们作为治疗靶点的潜力。此外，我们使用小鼠肿瘤模型进行的体内实验也验证了 XAI 衍生的假设，尤其是 IL27RA 在 HGSC 预后中的作用。这项研究不仅增进了我们对 HGSC 的了解，还说明了 XAI 在精准肿瘤学方面的潜力，为开发靶向疗法提供了更有效的途径。随着我们不断探索和完善这些方法，它们在不同癌症类型和临床环境中的应用前景十分广阔，为更个性化、更有效的癌症治疗铺平了道路。

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引用次数: 0

Immunologic tumor microenvironment modulators for turning cold tumors hot 让冷肿瘤变热的免疫肿瘤微环境调节剂

IF 16.2 1区医学 Q1 ONCOLOGY

Cancer Communications

Pub Date : 2024-03-29 DOI: 10.1002/cac2.12539

Gholam-Reza Khosravi, Samaneh Mostafavi, Sanaz Bastan, Narges Ebrahimi, Roya Safari Gharibvand, Nahid Eskandari

Tumors can be classified into distinct immunophenotypes based on the presence and arrangement of cytotoxic immune cells within the tumor microenvironment (TME). Hot tumors, characterized by heightened immune activity and responsiveness to immune checkpoint inhibitors (ICIs), stand in stark contrast to cold tumors, which lack immune infiltration and remain resistant to therapy. To overcome immune evasion mechanisms employed by tumor cells, novel immunologic modulators have emerged, particularly ICIs targeting cytotoxic T-lymphocyte-associated protein 4 (CTLA-4) and programmed cell death protein 1/programmed death-ligand 1(PD-1/PD-L1). These agents disrupt inhibitory signals and reactivate the immune system, transforming cold tumors into hot ones and promoting effective antitumor responses. However, challenges persist, including primary resistance to immunotherapy, autoimmune side effects, and tumor response heterogeneity. Addressing these challenges requires innovative strategies, deeper mechanistic insights, and a combination of immune interventions to enhance the effectiveness of immunotherapies. In the landscape of cancer medicine, where immune cold tumors represent a formidable hurdle, understanding the TME and harnessing its potential to reprogram the immune response is paramount. This review sheds light on current advancements and future directions in the quest for more effective and safer cancer treatment strategies, offering hope for patients with immune-resistant tumors.

根据肿瘤微环境（TME）中细胞毒性免疫细胞的存在和排列，可以将肿瘤分为不同的免疫分型。热肿瘤的特点是免疫活性增强，对免疫检查点抑制剂（ICIs）反应灵敏，与冷肿瘤形成鲜明对比，后者缺乏免疫浸润，对治疗仍有抵抗力。为了克服肿瘤细胞采用的免疫逃避机制，新型免疫调节剂应运而生，特别是针对细胞毒性T淋巴细胞相关蛋白4（CTLA-4）和程序性细胞死亡蛋白1/程序性死亡配体1（PD-1/PD-L1）的ICIs。这些药物能破坏抑制信号，重新激活免疫系统，将冷肿瘤转化为热肿瘤，促进有效的抗肿瘤反应。然而，挑战依然存在，包括免疫疗法的原发性耐药性、自身免疫副作用和肿瘤反应异质性。要应对这些挑战，需要创新的策略、更深入的机理研究以及综合的免疫干预措施，以提高免疫疗法的有效性。在癌症医学领域，免疫冷冻肿瘤是一个巨大的障碍，因此了解TME并利用其重新编程免疫反应的潜力至关重要。这篇综述揭示了在寻求更有效、更安全的癌症治疗策略方面的当前进展和未来方向，为免疫抗性肿瘤患者带来了希望。

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引用次数: 0

Single-cell landscape of malignant ascites from patients with metastatic colorectal cancer 转移性结直肠癌患者恶性腹水的单细胞图谱。

IF 20.1 1区医学 Q1 ONCOLOGY

Cancer Communications

Pub Date : 2024-03-26 DOI: 10.1002/cac2.12541

Haiyang Zhou, Jiahui Yin, Anqi Wang, Xiaomao Yin, Taojun Jin, Kai Xu, Lin Zhu, Jiexuan Wang, Wenqiang Wang, Wei Zhang, Xinxiang Li, Zhiqian Hu, Xinxing Li

The presence of malignant ascites in colorectal cancer (CRC) patients is associated with a poor prognosis, a high risk of recurrence, and resistance to chemotherapy and immune therapy [1-3]. Understanding the complex interactions among different kinds of cells and the ecosystem of peritoneal metastasized colorectal cancer (pmCRC) ascites may provide insights into effective treatment strategies.We profiled the single-cell transcriptomes of 96,065 cells from ascites samples of 12 treatment-naïve patients with pmCRC using the 10× single-cell RNA-sequencing (scRNA-seq) (Supplementary Figure S1A, Supplementary Table S1). Eleven major cell types were identified by characteristic canonical cell markers, including epithelial cells, endothelial cells, fibroblasts, T cells, B cells, monocytes, macrophages, plasma cells, natural killer (NK) cells, dendritic cells (DCs), and mast cells (Figure 1A-B). The main cellular components of pmCRC ascites are T cells (40,095; 41.7%), macrophages (28,487; 29.7%), and fibroblasts (5,932; 6.2%). Compared with primary CRC, which showed 14.8% epithelial cells [4], only 0.3% (291) epithelial cells were found in the ascites. The low percentage of epithelial cells in pmCRC ascites was consistent with the scRNA-seq studies of another tumor ascites [5-7].We classified the 12 patients into 2 groups according to their treatment response as follows: 8 patients (P02, P03, P04, P07, P08, P09, P11, and P12) had stable disease (SD), while 4 (P01, P05, P06, and P10) had progressive disease (PD). Single-cell transcriptomic analyses have revealed high heterogeneity of cell composition in 12 patients. The SD group exhibited a higher proportion of fibroblasts and epithelial cells (Figure 1B). Remarkably, fibroblasts had significantly different expression characteristics between the 2 groups (Figure 1C), and the top five upregulated/downregulated genes were visualized in 11 cell types (Figure 1D). We also found a significant increase in the frequency of macrophages in pmCRC ascites compared with the primary tumors [4] (Figure 1E). It hinted that significant inter-patient variability in the composition and functional programs of pmCRC ascites cells under different disease states.To comprehensively study the cellular interactions within the pmCRC ascites ecosystem, we predicted cell-cell communication networks using CellChat. Overall, we identified 44 significant ligand-receptor pair interactions. Although T cells were the most abundant cell population (41.7%) in pmCRC ascites, fibroblasts and macrophages were the core of the cellular interaction network (Figure 1F), suggesting their important roles in recruiting and cross-talking with diverse cells in the pmCRC ascites ecosystem.The result of cellular communications suggested that there was a complex interplay between various signaling molecule. Macrophage migration inhibitory factor (MIF), annexin, complement

结直肠癌（CRC）患者出现恶性腹水与预后不良、复发风险高以及对化疗和免疫疗法的耐药性有关 [1-3]。我们利用10×单细胞RNA测序技术（scRNA-seq）分析了12名未经治疗的pmCRC患者腹水样本中96,065个细胞的单细胞转录组（补充图S1A，补充表S1）。通过特征性的典型细胞标记鉴定出11种主要细胞类型，包括上皮细胞、内皮细胞、成纤维细胞、T细胞、B细胞、单核细胞、巨噬细胞、浆细胞、自然杀伤（NK）细胞、树突状细胞（DC）和肥大细胞（图1A-B）。pmCRC 腹水的主要细胞成分是 T 细胞（40,095；41.7%）、巨噬细胞（28,487；29.7%）和成纤维细胞（5,932；6.2%）。原发性 CRC 的上皮细胞比例为 14.8%[4]，而腹水中的上皮细胞比例仅为 0.3%（291 个）。pmCRC 腹水中上皮细胞的低比例与另一种肿瘤腹水的 scRNA-seq 研究一致[5-7]：根据治疗反应，我们将 12 名患者分为两组：8 名患者（P02、P03、P04、P07、P08、P09、P11 和 P12）病情稳定（SD），4 名患者（P01、P05、P06 和 P10）病情进展（PD）。单细胞转录组分析显示，12 名患者的细胞组成具有高度异质性。SD 组的成纤维细胞和上皮细胞比例较高（图 1B）。值得注意的是，成纤维细胞的表达特征在两组之间存在显著差异（图 1C），前五大上调/下调基因在 11 种细胞类型中均可视化（图 1D）。我们还发现，与原发肿瘤相比，pmCRC 腹水中巨噬细胞的频率明显增加[4]（图 1E）。为了全面研究 pmCRC 腹水生态系统中的细胞相互作用，我们使用 CellChat 预测了细胞-细胞通讯网络。总体而言，我们发现了 44 对重要的配体-受体相互作用。虽然T细胞是pmCRC腹水中数量最多的细胞群（41.7%），但成纤维细胞和巨噬细胞是细胞相互作用网络的核心（图1F），这表明它们在pmCRC腹水生态系统中与不同细胞的招募和交叉对话中发挥着重要作用。巨噬细胞迁移抑制因子（MIF）、附件蛋白、补体和C-C趋化因子配体（CCL）是CRC腹水中最活跃的传出/传入信号分子（补充图S1B）。成纤维细胞通过MIF-（CD74 + C-X-C 趋化因子受体4型 [CXCR4]）和MIF-（CD74 + CD44）轴的配体-受体相互作用以及C3-（整合素αX [ITGAX] + 整合素亚基β2 [ITGB2]）直接与不同类型的细胞接触（图1G）。值得注意的是，巨噬细胞群更有可能通过粘附配体-受体对 galectin-9 (LGALS9)-CD44 和 LGALS9-CD45 与其他细胞群相互作用，而在其他细胞群中没有观察到这种情况（图 1G）。在癌症基因组图谱（TCGA）的 CRC 队列中，CD74、LGALS9 与转移显著相关。我们还发现 CD44 和 ITGAX 具有生存性（图 1H；CD44 和 ITGAX 在转移性和非转移性患者之间没有明显的表达差异，因此数据未显示）。这些结果表明，pmCRC 腹水的整个细胞相互作用网络有助于建立免疫抑制和转移微环境。我们观察到，在 pmCRC 腹水样本中，SD 患者成纤维细胞的丰度明显高于 PD 患者（图 1B）。根据无监督聚类法，成纤维细胞被划分为 7 个不同的集群（C0-C6）（图 1I）。所有癌症相关成纤维细胞（CAfs）亚簇都显示了细胞外基质癌症相关成纤维细胞（eCAFs）特征的高表达（图 1J），而炎症性 CAF（iCAF）、肌成纤维细胞 CAF（myCAF）、基质 CAF（mCAF）和炎症性 CAF（iCAF）的表达都很高、而炎性CAF（iCAF）、肌成纤维细胞CAF（myCAF）和血管CAF（vCAF）只出现在一小部分成纤维细胞中（补充图S1C），这支持了eCAFs在增强pmCRC转移潜能中的作用。在PD队列（n = 310）中观察到的抗原呈递癌症相关成纤维细胞（apCAFs）的丰度高于SD队列（n = 93）（Wilcoxon检验，P = 0.049）。这些结果表明，pmCRC 腹水中的 CAFs 与免疫调节功能有双向关联，是治疗 CRC 的有利候选者。差异表达基因和基因本体（GO）分析表明，"细胞-细胞粘附"、"炎症反应 "和 "细胞因子产生 "在原发肿瘤和腹水中的富集程度不同（补充图 S1D），这意味着腹水的液态改变了成纤维细胞群的功能。利用之前定义的 "M1 "和 "M2 "特征，C2 显示出 "类 M1 "模式，C5 显示出 "类 M2 "模式。我们还发现 C5 中有一小部分同时表达 "M1 "和 "M2 "基因特征（图 1L），这在之前的实体瘤研究中已有报道[8]。接下来，我们检测了之前报道的一系列免疫抑制基因（白细胞相关免疫球蛋白样受体 1 [LAIR1]、甲型肝炎病毒细胞受体 2 [HAVCR2；又称 T 细胞免疫球蛋白和含粘蛋白结构域蛋白 3]、LGALS9 和 V 集免疫调节受体 [VSIR]）在巨噬细胞亚簇中的表达情况。由于 "M2 "标记基因 CD163 的表达模式与 LAIR1 在所有亚簇中的表达模式完全一致（图 1M），我们推测肿瘤相关巨噬细胞（TAMs）的免疫抑制功能可能是通过 LAIR1 发挥的。另外两个免疫抑制基因，即具有 Ig 和 ITIM 结构域的 T 细胞免疫受体（TIGIT）和程序性细胞死亡 1（PDCD1），也在 C5 中高表达。C4 高表达关键的免疫抑制表型标志物--髓系细胞上表达的触发受体 2（TREM2）（图 1N）。总之，pmCRC 腹水中的大多数巨噬细胞表现出高度免疫抑制特征。我们根据其各自标记物的表达确定了 11 个 T 细胞亚群，包括 CD4+ T 细胞（C1、C4、C5 和 C6）和 CD8+ T 细胞（C0、C2、C3、C7、C8、C9 和 C10）（图 1O）。大多数重新表达CD45RA T（Temra/Teff）细胞的CD8+效应记忆细胞（C8）来自患者5（P05），而CD8+效应记忆T（Tem）细胞（C7）主要来自患者8（P08）；其余10名患者的11个T细胞亚簇表现出高度异质性（补充图S1E-F）。重要的是，CD8+组织驻留记忆（Trm）细胞（C7）据报道与形成三级淋巴结构（TLS）有关[9]，但在SD患者（P03、P08、P09、P11和P12）中含量较少。我们还观察到，所有亚簇均表达铁蛋白轻链（FTL）（补充图 S1G），据报道，铁蛋白轻链可调控 CRC 的化疗耐药性和转移[10]。我们计算了所有 CD8+ T 细胞亚簇的细胞毒性、增殖和衰竭特征（图 1P）。只有一个 CD8+ T 细胞亚簇未显示衰竭特征（C10）。簇 9 和簇 10 的增殖率略高，这可能会招募细胞毒性 T 细胞。C9 和 C10 的丰度较低，这表明 T 细胞在腹水的免疫微环境中可能扮演次要角色，并可能与其他细胞群协同作用。此外，我们还预测了以巨噬细胞为靶点的免疫调节药物，从 pmCRC 腹水数据的巨噬细胞中提取了基因集（图 1Q）。总之，我们发现 T 细胞、成纤维细胞和巨噬细胞在 pmCRC 腹水中表现出免疫抑制特征（图 1R）。pmCRC腹水的细胞图谱对患者的免疫状态

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引用次数: 0

Immune cell pair ratio captured by imaging mass cytometry has superior predictive value for prognosis of non-small cell lung cancer than cell fraction and density 成像质控细胞仪捕获的免疫细胞对比率对非小细胞肺癌预后的预测价值优于细胞分数和密度。

IF 16.2 1区医学 Q1 ONCOLOGY

Cancer Communications

Pub Date : 2024-03-26 DOI: 10.1002/cac2.12540

Jian-Rong Li, Chao Cheng

Infiltrating immune cells in the tumor microenvironment (TME) play critical roles in the initiation, progression, and metastasis of cancer [1]. Previous studies have reported that the infiltration levels of various immune cell types are significantly associated with patient prognosis in different cancers [2, 3]. Specifically, in non-small cell lung cancer (NSCLC) the prognostic associations of major immune cell types have been investigated [4-6], however, some of the reported associations are inconsistent and remain debated [7]. Limited by technical issues, most studies focused on a few immune cell lineages or relied on inferred immune cell levels from computational deconvolution. To investigate the prognostic effects of all major immune cell types unbiasedly, more systematic high-quality immune cell profiling data with matched patient survival information are needed.Recently, Sorin et al. [8] used imaging mass cytometry (IMC) to characterize the immunological landscape of 416 distinct lung adenocarcinoma (LUAD) samples at single-cell resolution. The IMC images provide the counts and spatial distribution of 16 cell types with high precision in each sample. These cell types include cancer and endothelial cells, along with 14 immune cell types, including CD163+ and CD163− macrophages, CD8+, CD4+, regulatory, and other T cells, classical, non-classical, and intermediate monocytes, natural killer cells, dendritic cells, mast cells, neutrophils, and other immune cells. Additionally, the data provide patient survival and other clinical information. Using these data, we investigated the prognostic associations of the cell density (#cells/megapixel) and fractions of the 16 cell types as well as the fraction ratio between each pair of cell types (Supplementary Methods). Our results indicated that the relative abundance between cell types (fraction ratios) was more prognostic than cell fractions and densities.We calculated the densities of the 16 cell types in each patient's IMC image and applied Cox regression analysis to examine their associations with progression-free survival (PFS) after adjusting for established clinical factors including age, sex, smoking status, and tumor stage. At the significance level of P < 0.05, only the density of non-classical monocytes was found to have a significant association with worse prognosis (hazard ratio [HR] = 1.004, P = 0.040, Figure 1A). After multiple testing corrections, none of the cell types was significant (false discovery rate [FDR] > 0.05). Similar results were obtained when cell fractions among all cells were used for prognostic association analysis (Figure 1B). In addition, we conducted prognostic analysis on 14 immune cell types, focusing on their proportions among immune cells (excluding cancer and endothelial cells), yielding similar results. It has b

这些结果凸显了非经典或中间单核细胞与CD4+或CD8+T细胞的比例在LUAD中的关键预后作用，这与之前的研究显示非经典或中间单核细胞抑制CD8+或CD4+T细胞的增殖和免疫反应[9, 10]是一致的。为了进一步巩固我们的结果，我们进行了100次向下取样分析，每次随机选择80%的样本进行预后分析。就细胞密度和细胞分数而言，与 PFS 显著相关的细胞类型数量（FDR <0.05）平均分别只有 0.01 和 0.02（补充图 S4A）。相比之下，我们平均发现了 9.37 对重要的细胞-细胞对。此外，我们从所有图像中随机抽取了 80% 的细胞，并重新计算细胞分数进行预后分析，重复 100 次。平均每次发现 9.74 个重要的细胞对，而使用细胞分数和细胞密度则没有发现明显的关联（补充图 S4B）。总之，我们的研究证实，在 LUAD 中，预后价值与 TME 中特定细胞类型之间的相对丰度关系更密切，而不是 IMC 图像所显示的绝对细胞密度或细胞分数。这一发现强调了TME中不同免疫细胞之间相互作用的预后意义，尤其是免疫抑制细胞和免疫刺激细胞之间的免疫平衡。基于对免疫细胞相互作用的微妙理解，这些见解对开发靶向疗法和对LUAD患者进行分层具有重要意义。李建荣收集数据集。程超和李建荣进行了分析。李建荣绘制图表。程超和李建荣解释结果并撰写手稿。程超指导了该项目。本研究得到了德克萨斯州癌症预防研究所（CPRIT）（RR180061给CC）和美国国立卫生研究院国家癌症研究所（1R01CA269764给CC）的支持。CC 是 CPRIT 癌症研究学者。

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引用次数: 0

Cover Image, Volume 44, Issue 3 封面图片，第 44 卷第 3 期

IF 16.2 1区医学 Q1 ONCOLOGY

Cancer Communications

Pub Date : 2024-03-22 DOI: 10.1002/cac2.12537

Bin Song, Ping Yang, Shuyu Zhang

The cover image is based on the Review Article Cell fate regulation governed by p53: Friends or reversible foes in cancer therapy by Bin Song et al., https://doi.org/10.1002/cac2.12520.

封面图片基于宋斌等人撰写的评论文章《p53调控的细胞命运：癌症治疗中的朋友还是可逆的敌人》（Cell fate regulation governed by p53: Friends or reversible foes in cancer therapy），https://doi.org/10.1002/cac2.12520。

引用次数: 0

N6-methyladenosine reader hnRNPA2B1 recognizes and stabilizes NEAT1 to confer chemoresistance in gastric cancer N6-甲基腺苷阅读器 hnRNPA2B1 能识别并稳定 NEAT1，从而赋予胃癌化疗抗性。

IF 16.2 1区医学 Q1 ONCOLOGY

Cancer Communications

Pub Date : 2024-03-21 DOI: 10.1002/cac2.12534

Jiayao Wang, Jiehao Zhang, Hao Liu, Lingnan Meng, Xianchun Gao, Yihan Zhao, Chen Wang, Xiaoliang Gao, Ahui Fan, Tianyu Cao, Daiming Fan, Xiaodi Zhao, Yuanyuan Lu

Background

Chemoresistance is a major cause of treatment failure in gastric cancer (GC). Heterogeneous nuclear ribonucleoprotein A2B1 (hnRNPA2B1) is an N6-methyladenosine (m⁶A)-binding protein involved in a variety of cancers. However, whether m⁶A modification and hnRNPA2B1 play a role in GC chemoresistance is largely unknown. In this study, we aimed to investigate the role of hnRNPA2B1 and the downstream mechanism in GC chemoresistance.

Methods

The expression of hnRNPA2B1 among public datasets were analyzed and validated by quantitative PCR (qPCR), Western blotting, immunofluorescence, and immunohistochemical staining. The biological functions of hnRNPA2B1 in GC chemoresistance were investigated both in vitro and in vivo. RNA sequencing, methylated RNA immunoprecipitation, RNA immunoprecipitation, and RNA stability assay were performed to assess the association between hnRNPA2B1 and the binding RNA. The role of hnRNPA2B1 in maintenance of GC stemness was evaluated by bioinformatic analysis, qPCR, Western blotting, immunofluorescence, and sphere formation assays. The expression patterns of hnRNPA2B1 and downstream regulators in GC specimens from patients who received adjuvant chemotherapy were analyzed by RNAscope and multiplex immunohistochemistry.

Results

Elevated expression of hnRNPA2B1 was found in GC cells and tissues, especially in multidrug-resistant (MDR) GC cell lines. The expression of hnRNPA2B1 was associated with poor outcomes of GC patients, especially in those who received 5-fluorouracil treatment. Silencing hnRNPA2B1 effectively sensitized GC cells to chemotherapy by inhibiting cell proliferation and inducing apoptosis both in vitro and in vivo. Mechanically, hnRNPA2B1 interacted with and stabilized long noncoding RNA NEAT1 in an m⁶A-dependent manner. Furthermore, hnRNPA2B1 and NEAT1 worked together to enhance the stemness properties of GC cells via Wnt/β-catenin signaling pathway. In clinical specimens from GC patients subjected to chemotherapy, the expression levels of hnRNPA2B1, NEAT1, CD133, and CD44 were markedly elevated in non-responders compared with responders.

Conclusion

Our findings indicated that hnRNPA2B1 interacts with and stabilizes lncRNA NEAT1, which contribute to the maintenance of stemness property via Wnt/β-catenin pathway and exacerbate chemoresistance in GC.

背景：化疗耐药性是胃癌（GC）治疗失败的主要原因：耐药性是胃癌（GC）治疗失败的主要原因。异构核糖核蛋白 A2B1（hnRNPA2B1）是一种 N6-甲基腺苷（m6A）结合蛋白，与多种癌症有关。然而，m6A修饰和hnRNPA2B1是否在GC化疗耐药性中发挥作用，目前尚不清楚。本研究旨在探讨 hnRNPA2B1 在 GC 化疗耐药性中的作用及其下游机制：方法：通过定量 PCR（qPCR）、Western 印迹、免疫荧光和免疫组化染色等方法分析和验证了 hnRNPA2B1 在公开数据集中的表达情况。在体外和体内研究了 hnRNPA2B1 在 GC 化疗耐药性中的生物学功能。通过RNA测序、甲基化RNA免疫沉淀、RNA免疫沉淀和RNA稳定性检测来评估hnRNPA2B1与结合RNA之间的关联。通过生物信息分析、qPCR、Western 印迹、免疫荧光和球形成实验评估了 hnRNPA2B1 在维持 GC 干性中的作用。通过RNAscope和多重免疫组化分析了辅助化疗患者GC标本中hnRNPA2B1和下游调控因子的表达模式：结果：hnRNPA2B1在GC细胞和组织中的表达升高，尤其是在耐多药（MDR）GC细胞系中。hnRNPA2B1的表达与GC患者的不良预后有关，尤其是接受5-氟尿嘧啶治疗的患者。沉默hnRNPA2B1能在体外和体内抑制细胞增殖并诱导细胞凋亡，从而有效地使GC细胞对化疗敏感。在机制上，hnRNPA2B1与长非编码RNA NEAT1相互作用，并以m6A依赖性的方式稳定NEAT1。此外，hnRNPA2B1和NEAT1通过Wnt/β-catenin信号通路共同增强了GC细胞的干性。在接受化疗的GC患者的临床标本中，非应答者与应答者相比，hnRNPA2B1、NEAT1、CD133和CD44的表达水平明显升高：我们的研究结果表明，hnRNPA2B1与lncRNA NEAT1相互作用并使其稳定，从而通过Wnt/β-catenin通路维持干性特性，并加剧GC的化疗耐药性。

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引用次数: 0

Sexual dimorphism in the antitumor immune responses elicited by the combination of fasting and chemotherapy 禁食和化疗联合疗法引起的抗肿瘤免疫反应的性别双态性。

IF 16.2 1区医学 Q1 ONCOLOGY

Cancer Communications

Pub Date : 2024-03-21 DOI: 10.1002/cac2.12535

Andrés Pastor-Fernández, Manuel Montero Gómez de las Heras, Jose Ignacio Escrig-Larena, Marta Barradas, Cristina Pantoja, Adrian Plaza, Jose Luis Lopez-Aceituno, Esther Durán, Alejo Efeyan, Maria Mittelbrunn, Lola Martinez, Pablo Jose Fernandez-Marcos

Fasting reduces chemotherapy toxicity [1], enhances immunogenic tumor cell death [2, 3] and increases CD8+ T cell infiltration in tumors, particularly when combined with chemotherapy [2, 3] or immunotherapy [4]. Moreover, fasting exhibits a sexual dimorphism in the immune system [5].The aim of our study was to elucidate the role of sex in the beneficial anti-tumoral effects of combining fasting and chemotherapy. For this, we inoculated B16-F10-derived melanoma allografts into immunocompetent male and female mice. Three days later, the mice were divided into: (1) not treated; (2) two cycles of 48-hour fasting; (3) two cycles of 10 mg/kg doxorubicin; (4) two cycles of doxorubicin and fasting for 24 hours before and 24 hours after doxorubicin inoculation (“combination treatment” or “CT”). The study methods are shown in the Supplementary Material file. Doxorubicin and fasting alone reduced tumor growth in both sexes with the same efficacy, and CT amplified this effect only in males (Figure 1A and Supplementary Figure S1A-C). Male mice bearing YUMM1.7 melanoma-derived tumors responded to fasting and doxorubicin, but females were insensitive to any of them (Figure 1B and Supplementary Figure S2A-C). Oxaliplatin did not affect B16-F10 tumor growth (Supplementary Figure S3A-D). Fasting reduced serum levels of testosterone only in males ([6, 7] and Supplementary Figure S4A). To explore the role of testosterone, we castrated males or implanted testosterone pellets in females. CT lost efficacy in castrated males and became efficient in females with testosterone pellets (Figure 1C and Supplementary Figure S4B-E). Next, we inoculated mice with MC38 colon carcinoma cells [8]. Oxaliplatin or fasting reduced tumor growth, and CT amplified this effect in both sexes (Figure 1D and Supplementary Figure S5A-C). Our findings indicate that sexual dimorphism occurs in different tumor types, is dependent on tumor and chemotherapy type, and testosterone is a key player in this sexual dimorphism.To study the immune response in B16-F10 allografts treated with doxorubicin and/or fasting (Supplementary Figure S6A-D), we analyzed relevant immune cell types in inguinal lymph nodes (LN), peripheral blood (B) and tumors (T) (Supplementary Table S1-S4). CT increased stage II Natural Killer (NK) and Natural Killer T (NKT) cells in B16-F10 tumors only in males (Figure 1E-F and Supplementary Figure S6E-H). Females on CT had more exhausted CD8+ T cells in their tumors (Figure 1G and Supplementary Figure S6I-K). Tumor-infiltrated CD8+ T cells were functionally more active in CT in males (Supplementary Figure S7A-C), while serum TNFα did not change (Supplementary Figure S7D-E). Immunoablation of CD8 cells in male mice tended to reduce CT efficacy, which still improved the antitumor response (Supplementary Figure S8A-F and Supplementary Table S5),

禁食可减轻化疗毒性[1]，增强免疫原性肿瘤细胞死亡[2, 3]，增加CD8+ T细胞在肿瘤中的浸润，尤其是在与化疗[2, 3]或免疫疗法[4]联合使用时。我们的研究旨在阐明性别在禁食和化疗联合治疗的有益抗肿瘤效应中的作用。为此，我们将 B16-F10 黑色素瘤异种移植物接种到免疫功能正常的雌雄小鼠体内。三天后，小鼠被分为：（1）未接受治疗；（2）两个周期的 48 小时禁食；（3）两个周期的 10 毫克/千克多柔比星；（4）两个周期的多柔比星以及多柔比星接种前 24 小时和接种后 24 小时的禁食（"联合治疗 "或 "CT"）。研究方法见补充材料文件。单独使用多柔比星和禁食能以相同的疗效减少雌雄小鼠的肿瘤生长，而CT仅在雄性小鼠中扩大了这一效果（图1A和补充图S1A-C）。携带 YUMM1.7 黑色素瘤衍生肿瘤的雄性小鼠对禁食和多柔比星有反应，但雌性小鼠对任何一种药物都不敏感（图 1B 和补充图 S2A-C）。奥沙利铂不影响 B16-F10 肿瘤的生长（补充图 S3A-D）。空腹只降低了男性的血清睾酮水平（[6, 7]和补充图 S4A）。为了探究睾酮的作用，我们对雄性动物进行了阉割，或在雌性动物体内植入了睾酮颗粒。CT在阉割的雄性小鼠中失去了效力，而在植入睾酮颗粒的雌性小鼠中变得有效（图 1C 和补充图 S4B-E）。接着，我们给小鼠接种了 MC38 结肠癌细胞[8]。奥沙利铂或禁食可减少肿瘤的生长，而CT可放大这种效应（图1D和补充图S5A-C）。为了研究多柔比星和/或禁食治疗的 B16-F10 异体移植物的免疫反应（补充图 S6A-D），我们分析了腹股沟淋巴结（LN）、外周血（B）和肿瘤（T）中的相关免疫细胞类型（补充表 S1-S4）。CT仅在男性中增加了B16-F10肿瘤中的II期自然杀伤细胞（NK）和自然杀伤T细胞（NKT）（图1E-F和补充图S6E-H）。服用 CT 的女性肿瘤中有更多衰竭的 CD8+ T 细胞（图 1G 和补充图 S6I-K）。肿瘤浸润的 CD8+ T 细胞在男性 CT 中功能更活跃（补充图 S7A-C），而血清 TNFα 没有变化（补充图 S7D-E）。雄性小鼠的 CD8 细胞免疫消融往往会降低 CT 的疗效，但仍能改善抗肿瘤反应（补充图 S8A-F 和补充表 S5），这表明 CD8 细胞以外的免疫细胞群也参与了这种反应。补充图 S9A-L 和 S10A-J 显示了所有其他分析细胞群随着治疗和性别的变化。许多细胞因子和趋化因子的转录仅在雄性 CT 中强烈上调（补充图 S11A-B）。最后，我们用相同的方案处理了缺乏 T 淋巴细胞的雌雄 Hsd:Athymic Nude-Foxn1nu 小鼠。单独禁食并不能减少肿瘤的进展；单一化疗能减少肿瘤的生长，而CT主要能增强雄性小鼠的化疗效果（附图S12A-H）。这些结果表明，CT 的有益作用依赖于细胞免疫系统，尤其是 NK 和 NKT 细胞。然后，我们利用代表相关免疫群体的 17 个表面标记物对肿瘤中的免疫群体进行了高维分析（补充表 S6）。经过降维和无监督聚类，我们得到了 13 个免疫聚类（图 1H 和补充图 S13A），并量化了这些免疫细胞类型在不同实验组之间的差异（补充图 S13B）。簇 1（M2 巨噬细胞）在化疗中增加，而仅在男性 CT 中增加（补充图 S13C），与补充图 S10J 一致。表达衰竭标志物（TIM-3 和 PD-1）的第 4 组和第 13 组在接受 CT 的女性中往往较高（图 1I 和补充图 S13D），证实了图 1G 的结果。与单纯化疗相比，CT 中的第 7 组（I 期 NKT）在男女患者中均显著增加（补充图 S13E）。接下来，我们重点研究了 CD8+ T 细胞（补充图 S14A-B）。第 14 组（衰竭的中枢记忆/效应 CD8 细胞）在男女患者 CT 后都有所增加（补充图 S14C-D）。第 18 群和第 20 群（调节性 CD8 T 细胞 [9]）只有在男性单独接受化疗后才有减少的趋势（补充图 S14C 和 E）。这些发现强调了CD8细胞在两性之间对化疗和CT的不同反应。我们还检查了 NK1.1+ 细胞内的亚群，但没有发现有信息的亚群（补充图 S14F-G）。我们随后分析了携带 MC38 结肠癌细胞的小鼠的免疫群体（图 1D）。CT 增加了瘤内效应细胞和衰竭 CD8+ 细胞的总数（图 1J 和补充图 S15A-D）。与未治疗的小鼠相比，禁食、化疗和 CT 中的 CD8 肿瘤浸润更活跃（补充图 S15E-F）。CT 还增加了具有抗肿瘤特性的瘤内 CD4 Th1 细胞（图 1K 和补充图 S16A）。具有促癌特性的瘤内巨噬细胞总数随着 CT 的使用而减少（图 1L 和补充图 S16B）。补充图 S17-19 显示了两性中所有其他分析种群的演变情况，其中女性种群的表现与男性非常相似。肿瘤细胞因子和趋化因子的转录没有随治疗或性别发生显著变化（补充图 S20A-B）。利用 19 个表面标记物（补充表 S7）对瘤内免疫群体进行高维分析，然后进行降维和无监督聚类，产生了 15 个聚类（图 1M 和补充图 S21A）。簇1（M-MDSC）在化疗和CT中减少（补充图S21B-C）；簇2（PMN-MDSC）在CT中增加，尤其是在男性中（补充图S21B和D）；簇13（肿瘤相关巨噬细胞）在两种治疗和性别中均减少（图1N和补充图S21B）。我们分析了肿瘤排出的淋巴结和血液，以从生理学角度了解免疫反应。CT只增加了B16-F10雌性淋巴结MDSC（补充图S10B），这部分解释了雌性淋巴结MDSC未能对禁食产生反应，而这种变化并没有反映在肿瘤中（补充图S10A）。在 B16-F10 模型中，CT 增加了淋巴结相关的中央记忆细胞和幼稚 CD8 细胞，男女均如此（补充图 S9C-D），但这并没有反映在血液或肿瘤中。在 B16-F10 模型中，NK 和 NKT 细胞非常重要：在男性中，CT 使血液中的 NK 细胞减少，肿瘤中的 NK 细胞增加（补充图 S9E），而 II 期 NKT 细胞仅在肿瘤中增加（图 1F）。比较两种肿瘤模型，多柔比星减少了血液和淋巴结中的免疫细胞总数，而奥沙利铂没有减少（补充图 S9A 和 S17A）。这些结果表明，不同肿瘤类型的免疫系统有不同的整体反应，血液或淋巴结中的变化并不反映肿瘤中观察到的变化，这与之前的报道[10]不同。我们首次在这一过程中观察到了具有相关临床意义的性别二态性。最后，我们发现不同的肿瘤模型表现出不同的免疫反应，因此禁食对化疗的促进作用可能并不取决于特定的免疫群体（图1O）。曼努埃尔-蒙特罗-戈麦斯-德拉斯-赫拉斯（Manuel Montero Gómez de las Heras）和何塞-伊格纳西奥-埃斯克里格-拉雷纳（Jose Ignacio Escrig-Larena）：高维免疫方法学；形式分析和调查。Marta Barradas：免疫荧光研究设计与分析。克里斯蒂娜-潘托哈（Cristina Pantoja）：项目管理、数据采集和整理以及小鼠样本处理。Adrian Plaza：小鼠样本处理、调查和数据解读。Jose Luis Lopez-Aceituno：小鼠样本处理和

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引用次数: 0