Cyrus M. GhajarAna Luisa CorreiaJulio A. Aguirre-GhisoShang Cai...
5页
查看更多>>摘要：Metastasis, the major cause of cancer death, represents one of the major challenges in oncology. Scientists are still trying to understand the biological basis underlying the dissemination and outgrowth of tumor cells, why these cells can remain dormant for years, how they become resistant to the immune system or cytotoxic effects of systemic therapy, and how they interact with their new microenvironment. We asked experts to discuss some of the unknowns, advances, and areas of opportunity related to cancer metastasis.
查看更多>>摘要：Transposable elements (TEs), which make up almost half of the human genome, often display altered expression in cancers. Here, we review recent progress in elucidating the role of TEs as mediators of immune responses in cancer and discuss how novel therapeutic strategies can harness TE immunogenicity for cancer immunotherapy. Transposable elements (TEs) are current or previous mobile elements within the genome. In humans, they constitute 46% of the genome and are classified into two main types: DNA transposons and retroelements. Retroelements are further divided into three broad subclasses: long interspersed nuclear elements (LINEs), short interspersed nuclear elements (SINEs), and long terminal repeat (LTR)/endogenous retrovirus (ERV) elements (Figure 1A).
Anneloes van KrimpenVivian I.V. GerretsenEvalyn E.A.P. MulderMy van Gulijk...
2页
查看更多>>摘要：Immune checkpoint blockade (ICB) using anti-PD-1/PD-L1 and anti-CTLA-4 antibodies significantly enhances survival in metastatic melanoma patients and has recently been shown to prolong relapse-free survival in stage III and high-risk stage II melanoma patients (Eggermont et al., 2018; Luke et al., 2022; Robert et al., 2015). However, a significant proportion of patients does not respond to ICB prior to or following surgery, for reasons incompletely understood. We and others recently identified tumor-draining lymph nodes (TDLNs) to be critically involved in anti-PD-L1 treatment efficacy in preclinical tumor models (Dammeijer et al., 2020; Fransen et al., 2018). Furthermore, we found that abundant PD-1 andPD-L1 interactions in TDLNs of patients with non-met -astatic melanoma at presentation were associated with distant disease recurrence, suggesting that immune suppression in TDLNs might prevent a durable and effective systemic anti-tumor immune response. However, it remains incompletely understood which cells and pathways-including their spatial tissue localization-within TDLNs promote disease recurrence in melanoma. Here, we address these issues by analyzing the immune composition in TDLNs of stage III melanoma patients using multiplexed gene expression analysis, digital spatial profiling (DSP), and multi-color confocal imaging.
Sidse EhmsenAnders AsmussenStefan S. JeppesenAnna Christine Nilsson...
2页
查看更多>>摘要：Patients with cancer are at increased risk of severe COVID-19 disease because of immunosuppression caused by the cancer and/or cancer treatments (Ehmsen et al., 2021b; Tian et al., 2020). We and others have characterized the anti-SARS-CoV-2 immune response after two and three COVID-19 mRNA vaccinations in patients with solid and hematologic cancers and observed insufficient responses in a substantial portion following the second vaccination ((Ehmsen et al., 2021a; Gounant et al., 2022; Herishanu et al., 2022) but an improved response following the third vaccination (Ehmsen et al., 2022). We further showed that the anti-SARS-CoV-2 spike receptor binding domain (anti-S) IgG antibody titers declined rapidly within the first 3 months after both the second and third vaccination. This, in combination with high infectivity rate of COVID-19 in the population in the winter of 2021-2022, made the Health Authorities in several countries, including Denmark, recommend a fourth mRNA COVID-19 vaccination to boost the immune response in this patient group. Here, we assess alterations in antibody titers (anti-S IgG) in blood samples following a fourth mRNA vaccination from patients with solid and hematologic malignancies, and we assess the waning antibody response at 3 months following the fourth vaccination.
查看更多>>摘要：Pancreatic ductal adenocarcinoma is characterized by a complex microenvironment. In this issue of Cancer Cell, Chen and colleagues define an oncogenic role of tumor-cell-produced collagen I homotrimers, wherein tumor development is promoted by integrin alpha3/beta1 -dependent activation of tumor cell signaling and modulation of tumor microbiome and immunity. Solid tumors develop as abnormal tissue ecosystems with an irregular extracellular matrix (ECM) that establishes a bio-physically and biochemically pro-tumori-genic environment (Cox, 2021). This is particularly evident in pancreatic ductal adenocarcinoma (PDAC), in which the majority of the tumor is made up of host stromal cells and an abundant ECM, such that malignant cells constitute less than 15% of the tumor on average (Ho et al., 2020). Pleiotropic tumor-promoting effects have been ascribed to the stiffened ECM, and these effects include activation of mechano-signaling pathways to augment oncogenic signaling, retention of growth factors and cytokines to alter local biochemical signaling pathways, supplying nutrients for tumor cells, and driving an increase in the interstitial pressure that collapses vessels and thus impedes blood flow (Ho et al., 2020).
查看更多>>摘要：Morphology, immunophenotype, cytogenetics, and genomics have long dominated diagnostics in acute my-elogenous leukemia (AML). In this issue of Cancer Cell, Bottomly et al. demonstrate that combining the above with transcriptomics and ex vivo drug testing of patient myeloblasts yields novel diagnostic and therapeutic insights with the potential for clinical translation.
查看更多>>摘要：Meaningful integration of artificial intelligence (AI) will transform the application of ‘‘big data’’ for patient care, diagnosis, and research. In this issue of Cancer Cell, Chen et al. describe a transparent system to integrate histopathology and molecular data to predict outcomes and identify novel biomarkers in cancer. In the past decade, artificial intelligence (AI) approaches have achieved preeminence in data analysis from large, complex datasets such as digital images, e.g., radiology, digitized pathology slides (whole-slide images [WSIs]), and molecular data. Methods combining molecular and image data are not in common use, and as technology has improved, there is increased interest in extracting features from the data-rich material of archival pathology tissue slides. Early AI applications in histopathology included relatively simple supervised tasks such as counting of positive immunohistochemical stained cells to create accurate proliferation indices for cancer classification and grading (Kolles et al., 1995; Saha et al., 2017). More sophisticated models allow recognition of histologic patterns with known prognostic impact, e.g., Gleason score in prostate adenocarcinoma (Bulten et al., 2022). With larger datasets and improved learning algorithms, AI can Elsevier Inc.
查看更多>>摘要：In this issue of Cancer Cell, Zaitsev et al. (2022) present a machine-learning-based approach, trained from millions of artificial transcriptomes with admixed cell populations, for reconstructing tumor microenvironments (TMEs). The high accuracy of this approach, demonstrated through extensive validation, enables systematic investigation of TMEs in both research and clinical settings. Understanding the tumor microenviron-ment (TME) is critical for exploring the therapeutical potential and rational design of immunotherapy (Wei et al., 2018). Many computational methods have been developed to deconvolute transcriptome sequencing (RNA-seq) data generated from bulk tumor samples, which has greatly advanced our understanding of TME cellular composition in recent years (Thorsson et al., 2018). Existing methods were primarily designed to model cell type-specific gene expression profiles (Newman et al., 2015) or to perform deep learning using single-cell RNA-seq (scRNA-seq) of the same tissue type (Newman et al., 2019; Menden et al., 2020). Therefore, they are not optimized for capturing rare or hierarchical TME subpopulations and have limited applications in samples that lack scRNA-seq or flow cytometry data.
查看更多>>摘要：A Cell article reports that lymph node metastases can suppress the immune system, thereby promoting further cancer spread in mouse models; this is corroborated in patients as described in a letter in this issue of Cancer Cell. The lymph node thus actively generates a cancer-permissive environment and is an untapped target to manipulate the immune system. ‘‘One bad apple can spoil the bunch’’ is a common proverb that warns of the active influence of rotting fruit. Perishing produce passively warns us of the impending decay of other produce harvested at a similar time. But rotting produce releases ethylene, a development hormone, through skin breaks and forces neighboring fruit to quickly mature. In an article recently published in Cell, Reticker-Flynn et al. (2022) demonstrate that a tumor-infiltrated lymph node, like a bad apple, can prime the environment toward undesirable consequences.
查看更多>>摘要：In a recent publication in Nature, Fane et al. establish WNT5A as a central, age-sensitive regulator of the dormancy-to-reactivation axis of melanoma. They show that aged fibroblasts in the lungs suppress WNT5A signaling induced at the primary tumor site to awaken dormant melanoma cells and promote the outgrowth of metastases. Aging is associated with increased cancer incidence and disease-related mortality (Macdonald et al., 2011). Factors that contribute to a higher cancer incidence in older adults include decreased immune surveillance, mutational accumulation, and changes in the tissue microenvironment. Cancer cells that disseminate from the primary tumor and settle in distant locations may lie dormant for years before re-emerging to form metastases. Detection of these sparse and dormant micro-metastases is nearly impossible without established biomarkers. Therefore, further knowledge of the factors that regulate tumor dormancy and reactivation is needed in order to understand why older cancer patients are at increased risk for disease recurrence (Macdonald et al., 2011).
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