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- Volume 6, 2022
Annual Review of Cancer Biology - Volume 6, 2022
Volume 6, 2022
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The Metabolic Relationship Between Viral Infection and Cancer
Vol. 6 (2022), pp. 1–15More LessViruses are fundamental tools in cancer research. They were used to discover the first oncogenes in the 1970s, and they are now being modified for use as antitumor therapeutics. Key to both of these oncogenic and oncolytic properties is the ability of viruses to rewire host cell metabolism. In this review, we describe how viral oncogenes alter metabolism to increase the synthesis of macromolecules necessary for both viral replication and tumor growth. We then describe how understanding the specific metabolic requirements of virus-infected cells can help guide strategies to improve the efficacy of oncolytic viruses, and we highlight immunometabolism and tumor microenvironment research that could also increase the therapeutic benefits of oncolytic viruses. We also describe how studies describing the therapeutic effects of dietary nutrient restriction in cancer can suggest new avenues for research into antiviral therapeutics.
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Targeting Solid Tumors with Bispecific T Cell Engager Immune Therapy
Vol. 6 (2022), pp. 17–34More LessT cell engagers (TCEs) are targeted immunotherapies that have emerged as a promising treatment to redirect effector T cells for tumor cell killing. The strong therapeutic value of TCEs, established by the approval of blinatumomab for the treatment of B cell precursor acute lymphoblastic leukemia, has expanded to include other hematologic malignancies, as well as some solid tumors. Successful clinical development of TCEs in solid tumors has proven challenging, as it requires additional considerations such as the selectivity of target expression, tumor accessibility, and the impact of the immunosuppressive tumor microenvironment. In this review, we provide a brief history of blinatumomab, summarize learnings from TCEs in hematologic malignancies, and highlight results from recent TCE trials in solid tumors. Additionally, we examine approaches to improve the efficacy and safety of TCEs in solid tumors, including therapeutic combinations to increase the depth and durability of response.
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Tracing and Targeting the Origins of Childhood Cancer
Vol. 6 (2022), pp. 35–47More LessDespite the success of treating childhood cancers with cytotoxic agents, novel therapeutic strategies are required to achieve the next leap in cure rates. A promising avenue may be to target the origin of childhood cancers. Here, we review recent advances in tracing the origins of pediatric tumors. Cancer-to-normal cell comparisons by single-cell mRNA sequencing reveal the fetal state of cancer cells, as well as their cell of origin. Recent phylogenetic analyses have uncovered large tissue-resident precursor clones to childhood cancers, which already possess key genomic alterations leading to tumor formation. Both the transcriptional fetalness and genomic status of the premalignant tissue bed provide further avenues for targeted therapy. Overall, these advances begin to describe the precise origins of pediatric tumors and pave the way for novel methods in detecting, treating, and perhaps even preventing childhood cancers.
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Targeting KRAS G12C with Covalent Inhibitors
Vol. 6 (2022), pp. 49–64More LessKRAS is the most frequently mutated oncogene in cancer. Following numerous attempts to inhibit KRAS spanning multiple decades, recent efforts aimed at covalently targeting the mutant cysteine of KRAS G12C have yielded very encouraging results. Indeed, one such molecule, sotorasib, has already received accelerated US Food and Drug Administration approval with phase III clinical trials currently underway. A second molecule, adagrasib, has also progressed to phase III, and several others have entered early-phase clinical trials. The success of these efforts has inspired an array of novel approaches targeting KRAS, with some reporting extension to the two most common oncogenic KRAS mutations, G12V and G12D.
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Gut Microbiota in Colorectal Cancer: Associations, Mechanisms, and Clinical Approaches
Vol. 6 (2022), pp. 65–84More LessColorectal cancer (CRC) is associated with the presence of particular gut microbes, as observed in many metagenomic studies to date. However, in most cases, it remains difficult to disentangle their active contribution to CRC from just a bystander role. This review focuses on the mechanisms described to date by which the CRC-associated microbiota could contribute to CRC. Bacteria like pks+ Escherichia coli, Fusobacterium nucleatum, or enterotoxigenic Bacteroides fragilis have been shown to induce mutagenesis, alter host epithelial signaling pathways, or reshape the tumor immune landscape in several experimental systems. The mechanistic roles of other bacteria, as well as newly identified fungi and viruses that are enriched in CRC, are only starting to be elucidated. Additionally, novel systems like organoids and organs-on-a-chip are emerging as powerful tools to study the direct effect of gut microbiota on healthy or tumor intestinal epithelium. Thus, the expanding knowledge of tumor-microbiota interactions holds promise for improved diagnosis and treatment of CRC.
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Central Role of the Antigen-Presentation and Interferon-γ Pathways in Resistance to Immune Checkpoint Blockade
Vol. 6 (2022), pp. 85–102More LessResistance to immunotherapy is due in some instances to the acquired stealth mechanisms of tumor cells that lose expression of MHC class I antigen–presenting molecules or downregulate their class I antigen–presentation pathways. Most dramatically, biallelic β2-microglobulin (B2M) loss leads to complete loss of MHC class I expression and to invisibility to CD8+ T cells. MHC class I expression and antigen presentation are potently upregulated by interferon-γ (IFNγ) in a manner that depends on IFNγ receptor (IFNGR) signaling via JAK1 and JAK2. Mutations in these molecules lead to IFNγ unresponsiveness and mediate loss of recognition and killing by cytotoxic T lymphocytes. Loss of MHC class I augments sensitivity of tumor cells to be killed by natural killer (NK) lymphocytes, and this mechanism could be exploited to revert resistance, for instance, with interleukin-2 (IL-2)-based agents. Moreover, in some experimental models,potent local type I interferon responses, such as those following intratumoral injection of Toll-like receptor 9 (TLR9) or TLR3 agonists, revert resistance due to mutations of JAKs.
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CRISPR Screens to Identify Regulators of Tumor Immunity
Vol. 6 (2022), pp. 103–122More LessCancer immunotherapies, such as immune checkpoint blockade (ICB), have been used in a wide range of tumor types with immense clinical benefit. However, ICB does not work in all patients, and attempts to combine ICB with other immune-based therapies have not lived up to their initial promise. Thus, there is a significant unmet need to discover new targets and combination therapies to extend the benefits of immunotherapy to more patients. Systems biology approaches are well suited for addressing this problem because these approaches enable evaluation of many gene targets simultaneously and ranking their relative importance for a phenotype of interest. As such, loss-of-function CRISPR screens are an emerging set of tools being used to prioritize gene targets for modulating pathways of interest in tumor and immune cells. This review describes the first screens performed to discover cancer immunotherapy targets and the technological advances that will enable next-generation screens.
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TGFβ: Signaling Blockade for Cancer Immunotherapy
Vol. 6 (2022), pp. 123–146More LessDiscovered over four decades ago, transforming growth factor β (TGFβ) is a potent pleiotropic cytokine that has context-dependent effects on most cell types. It acts as a tumor suppressor in some cancers and/or supports tumor progression and metastasis through its effects on the tumor stroma and immune microenvironment. In TGFβ-responsive tumors it can promote invasion and metastasis through epithelial-mesenchymal transformation, the appearance of cancer stem cell features, and resistance to many drug classes, including checkpoint blockade immunotherapies. Here we consider the biological activities of TGFβ action on different cells of relevance toward improving immunotherapy outcomes for patients, with a focus on the adaptive immune system. We discuss recent advances in the development of drugs that target the TGFβ signaling pathway in a tumor-specific or cell type–specific manner to improve the therapeutic window between response rates and adverse effects.
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Development of Tissue-Agnostic Treatments for Patients with Cancer
Vol. 6 (2022), pp. 147–165More LessIn 2017 the FDA (US Food and Drug Administration) approved pembrolizumab, a programmed death 1 (PD-1) inhibitor, for the treatment of unresectable or metastatic, microsatellite instability–high (MSI-H) or mismatch repair–deficient (dMMR) solid tumors, regardless of tumor site or histology. This represented the first approval based on the identification of a biomarker and independent of tumor site. Although this approach may intuitively appear rational, tissue-agnostic drug development can be complicated by tumor-specific resistance mechanisms or other factors that can alter a drug's effect. Inherent with the tissue-agnostic approach is the fact that there may be residual uncertainty concerning a drug's effect in unstudied tumor types (e.g., at the time of approval). However, this approach may be the only available mechanism to support approval and provide access to a drug that is indicated for the treatment of patients with certain rare biomarker-positive cancers.
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Single-Cell Epigenomics Reveals Mechanisms of Cancer Progression
Vol. 6 (2022), pp. 167–185More LessCancer initiation is driven by the cooperation between genetic and epigenetic aberrations that disrupt gene regulatory programs critical to maintaining specialized cellular functions. After initiation, cells acquire additional genetic and epigenetic alterations influenced by tumor-intrinsic and -extrinsic mechanisms, which increase intratumoral heterogeneity, reshape the cell's underlying gene regulatory networks and promote cancer evolution. Furthermore, environmental or therapeutic insults drive the selection of heterogeneous cell states, with implications for cancer initiation, maintenance, and drug resistance. The advancement of single-cell genomics has begun to uncover the full repertoire of chromatin and gene expression states (cell states) that exist within individual tumors. These single-cell analyses suggest that cells diversify in their regulatory states upon transformation by co-opting damage-induced and nonlineage regulatory programs that can lead to epigenomic plasticity. Here, we review these recent studies related to regulatory state changes in cancer progression and highlight the growing single-cell epigenomics toolkit poised to address unresolved questions in the field.
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Clonal Hematopoiesis: Confluence of Malignant and Nonmalignant Diseases
Vol. 6 (2022), pp. 187–200More LessClonal hematopoiesis of indeterminate potential (CHIP) is a state in which somatic mutations in hematopoietic stem cells lead to clonal expansion of blood cells in individuals without hematologic malignancy. The mutated genes, including TET2, DNMT3A, ASXL1, TP53, JAK2, and SF3B1, are also recurrently mutated in myeloid malignancies. Individuals with CHIP have an increased risk of developing a hematologic cancer. Moreover, individuals with CHIP have an elevated risk of all-cause mortality that is significantly attributable to cardiovascular disease, independent of traditional risk factors. The mechanism for this increased risk is likely linked to increased inflammation driven by mutated macrophages, in part through inflammasome activation. This has broadened our understanding of how chronic diseases are influenced by CHIP and of the mechanistic role of inflammation in these disorders.
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RB1, Cancer Lineage Plasticity, and Therapeutic Resistance
Vol. 6 (2022), pp. 201–221More LessLineage plasticity, a cell's capacity to switch lineage-restricted gene expression states, is required for normal tissue homeostasis. Cancer lineage plasticity is increasingly observed as a mechanism of resistance to therapy, particularly molecularly targeted therapies. These therapies often owe their superior efficacy to the lineage-restricted nature of their therapeutic target, so cancers can evade such therapies by changing lineage states. As increasingly effective molecularly targeted therapies are deployed, cancer lineage plasticity is likely to be a growing clinical problem. Lineage plasticity reflects a nongenetic, potentially reversible transcriptional adaptation, but oncogenic genetic mutations likely drive elevated lineage plasticity that is typical of cancer cells. Here key concepts relevant to cancer lineage plasticity are presented, evidence implicating loss of the RB1 tumor-suppressor gene in driving cancer lineage plasticity is reviewed, and possible therapeutic approaches to counter cancer lineage plasticity are discussed.
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Caught in a Web: Emerging Roles of Neutrophil Extracellular Traps in Cancer
Xue-Yan He, David Ng, and Mikala EgebladVol. 6 (2022), pp. 223–243More LessNeutrophil extracellular traps (NETs) are meshes of DNA decorated with granular proteins that are extruded from neutrophils during immune responses to pathogens. However, excessive NET formation is negatively associated with many diseases, including cancer. NETs contain, for example, proteases, danger-associated molecular patterns (DAMPs), and DNA. These components can act directly on the cancer cells but also affect the surrounding microenvironment, including altering the extracellular matrix and the immune response to tumors. Here, we discuss the emerging roles of NETs in cancer progression, from their ability to promote primary tumor growth and immune escape to their prometastatic effects. The potential clinical implication of targeting NETs as novel therapeutic strategies in cancer is also discussed.
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Cancer Genomic Rearrangements and Copy Number Alterations from Errors in Cell Division
Vol. 6 (2022), pp. 245–268More LessAnalysis of cancer genomes has shown that a large fraction of chromosomal changes originate from catastrophic events including whole-genome duplication, chromothripsis, breakage-fusion-bridge cycles, and chromoplexy. Through sophisticated computational analysis of cancer genomes and experimental recapitulation of these catastrophic alterations, we have gained significant insights into the origin, mechanism, and evolutionary dynamics of cancer genome complexity. In this review, we summarize this progress and survey the major unresolved questions, with particular emphasis on the relative contributions of chromosome fragmentation and DNA replication errors to complex chromosomal alterations.
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Novel Mouse Models for Cancer Immunology
Vol. 6 (2022), pp. 269–291More LessMouse models of cancer immunology provide excellent systems in which to study and test biological mechanisms of the immune response against cancer. Historically, these models were designed to have different strengths based on the current major research questions at the time. As such, many mouse models of immunology used today were not originally developed to study current questions in the relatively new field of cancer immunology, but instead have been adapted for such purposes. In this review, we discuss various mouse models of cancer immunology in a historical context in order to provide a fuller perspective of each model's strengths. From this outlook, we discuss the current state of the art and strategies for tackling future modeling challenges.
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Oncohistones: Hijacking the Histone Code
Varun Sahu, and Chao LuVol. 6 (2022), pp. 293–312More LessChromatin dysfunction has been implicated in a growing number of cancers especially in children and young adults. In addition to chromatin-modifying and -remodeling enzymes, mutations in histone genes are linked to human cancers. Since the first reports of hotspot missense mutations affecting key residues at the histone H3 tail, studies have revealed how these so-called oncohistones dominantly (H3K27M and H3K36M) or locally (H3.3G34R/W) inhibit corresponding histone methyltransferases and misregulate epigenome and transcriptome to promote tumorigenesis. More recently, widespread mutations in all four core histones are identified in diverse cancer types. Furthermore, an oncohistone-like protein EZHIP has been implicated in driving childhood ependymomas through a mechanism highly reminiscent of H3K27M mutation. Here we review recent progress in understanding the biochemical, molecular, and biological mechanisms underlying the canonical and novel histone mutations. Importantly, these mechanistic insights have identified therapeutic opportunities for oncohistone-driven tumors.
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Targeting BET Bromodomains in Cancer
Vol. 6 (2022), pp. 313–336More LessCancer is frequently dependent on aberrant gene expression programs that might be vulnerable to targeting with novel therapeutics. Bromodomain and extraterminal domain (BET) proteins are powerful transcriptional coregulators often found as part of oncogenic transcriptional programs. The bromodomain functionality of BET proteins is highly druggable, and several product candidates are in clinical testing. While initial clinical data created doubt about their benefit for cancer patients, more encouraging data recently reported in myelofibrosis patients may promote additional applications of BET inhibitors in oncology as monotherapy and in combination with other therapeutic agents. Moreover, a growing number of approaches to optimize the therapeutic window by tinkering with the property profiles of BET inhibitors may provide additional clinical opportunities. This review provides an update on the status of ongoing activities to exploit BET bromodomain inhibition as a mechanism for cancer therapy.
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