CRISPR Screens to Identify Regulators of Tumor Immunity

2021 ◽  
Vol 6 (1) ◽  
Author(s):  
Martin W. LaFleur ◽  
Arlene H. Sharpe
Keyword(s):  
Cancer Biology ◽  
Unmet Need ◽  
Immune Checkpoint Blockade ◽  
Annual Review ◽  
Publication Date ◽  
Loss Of Function ◽  
Technological Advances ◽  
Wide Range ◽  
Tumor Types ◽  
Cancer Immunotherapies

Cancer 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. Expected final online publication date for the Annual Review of Cancer Biology, Volume 6 is April 2022. Please see http://www.annualreviews.org/page/journal/pubdates for revised estimates.

scholarly journals Myeloid-Derived Suppressor Cells: Facilitators of Cancer and Obesity-Induced Cancer

2020 ◽  
Vol 5 (1) ◽  
Author(s):  
Suzanne Ostrand-Rosenberg
Keyword(s):  
Cancer Biology ◽  
Suppressor Cells ◽  
Annual Review ◽  
Publication Date ◽  
Rapid Progression ◽  
Myeloid Derived Suppressor Cells ◽  
Multiple Tumor ◽  
Immature Myeloid Cells ◽  
Key Aspects ◽  
Cancer Immunotherapies

Immature myeloid cells at varied stages of differentiation, known as myeloid-derived suppressor cells (MDSC), are present in virtually all cancer patients. MDSC are profoundly immune-suppressive cells that impair adaptive and innate antitumor immunity and promote tumor progression through nonimmune mechanisms. Their widespread presence combined with their multitude of protumor activities make MDSC a major obstacle to cancer immunotherapies. MDSC are derived from progenitor cells in the bone marrow and traffic through the blood to infiltrate solid tumors. Their accumulation and suppressive potency are driven by multiple tumor- and host-secreted proinflammatory factors and adrenergic signals that act via diverse but sometimes overlapping transcriptional pathways. MDSC also accumulate in response to the chronic inflammation and lipid deposition characteristic of obesity and contribute to the more rapid progression of cancers in obese individuals. This article summarizes the key aspects of tumor-induced MDSC with a focus on recent progress in the MDSC field. Expected final online publication date for the Annual Review of Cancer Biology, Volume 5 is March 4, 2021. Please see http://www.annualreviews.org/page/journal/pubdates for revised estimates.

scholarly journals The Intriguing Clinical Success of BCL-2 Inhibition in Acute Myeloid Leukemia

2020 ◽  
Vol 5 (1) ◽  
Author(s):  
Daniel A. Pollyea ◽  
Shanshan Pei ◽  
Brett M. Stevens ◽  
Clayton A. Smith ◽  
Craig T. Jordan
Keyword(s):  
Acute Myeloid Leukemia ◽  
Myeloid Leukemia ◽  
Cancer Biology ◽  
Clinical Success ◽  
Annual Review ◽  
Publication Date ◽  
Combined Use ◽  
Wide Range ◽  
Preclinical And Clinical Studies ◽  
Acute Myeloid

Over the past several decades numerous preclinical and clinical studies have pursued new approaches for the treatment of acute myeloid leukemia (AML). While some degree of clinical response has been demonstrated for many therapies, for the most part, fundamental changes in the treatment landscape have been lacking. Recently, the use of the BCL-2 inhibitor venetoclax has emerged as a potent therapy for a majority of newly diagnosed AML patients. Venetoclax regimens have shown broad response rates with deep and durable remissions, with a superior toxicity profile compared with traditional intensive chemotherapy agents. Numerous ongoing studies are now using venetoclax in combination with a wide range of other agents as investigators seek even more effective and well-tolerated regimens. Notably, however, while the empirical results of BCL-2 inhibition are encouraging, the mechanisms that have led to these successful clinical outcomes remain unclear. Intriguingly, the activity of venetoclax in AML patients appears to go beyond simply modulating canonical antiapoptosis mechanisms; in addition, the efficacy of venetoclax is linked to its combined use with conventional low-intensity backbone therapies. This article will evaluate the state of the field, provide a summary of key considerations, and propose directions for future studies. Expected final online publication date for the Annual Review of Cancer Biology, Volume 5 is March 4, 2021. Please see http://www.annualreviews.org/page/journal/pubdates for revised estimates.

Electronic, Ionic, and Mixed Conduction in Polymeric Systems

2021 ◽  
Vol 51 (1) ◽  
Author(s):  
Elayne M. Thomas ◽  
Phong H. Nguyen ◽  
Seamus D. Jones ◽  
Michael L. Chabinyc ◽  
Rachel A. Segalman
Keyword(s):  
Materials Science ◽  
Transport Coefficients ◽  
Polymeric Materials ◽  
Annual Review ◽  
Publication Date ◽  
Energy Storage Devices ◽  
Polymeric Systems ◽  
Storage Devices ◽  
Technological Advances ◽  
Performance Benchmark

Polymers that simultaneously transport electrons and ions are paramount to drive the technological advances necessary for next-generation electrochemical devices, including energy storage devices and bioelectronics. However, efforts to describe the motion of ions or electrons separately within polymeric systems become inaccurate when both species are present. Herein, we highlight the basic transport equations necessary to rationalize mixed transport and the multiscale materials properties that influence their transport coefficients. Potential figures of merit that enable a suitable performance benchmark in mixed conducting systems independent of end application are discussed. Practical design and implementation of mixed conducting polymers require an understanding of the evolving nature of structure and transport with ionic and electronic carrier density to capture the dynamic disorder inherent in polymeric materials. Expected final online publication date for the Annual Review of Materials Science, Volume 51 is July 2021. Please see http://www.annualreviews.org/page/journal/pubdates for revised estimates.

Central Role of the Antigen-Presentation and Interferon-γ Pathways in Resistance to Immune Checkpoint Blockade

2021 ◽  
Vol 6 (1) ◽  
Author(s):  
Annette Paschen ◽  
Ignacio Melero ◽  
Antoni Ribas
Keyword(s):  
Antigen Presentation ◽  
Tumor Cells ◽  
Mhc Class I ◽  
Cancer Biology ◽  
Interleukin 2 ◽  
Interferon Γ ◽  
Class I ◽  
Annual Review ◽  
Publication Date ◽  
Type I

Resistance 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. Expected final online publication date for the Annual Review of Cancer Biology, Volume 6 is April 2022. Please see http://www.annualreviews.org/page/journal/pubdates for revised estimates.

TGFβ: Signaling Blockade for Cancer Immunotherapy

2021 ◽  
Vol 6 (1) ◽  
Author(s):  
Szu-Ying Chen ◽  
Ons Mamäi ◽  
Rosemary J. Akhurst
Keyword(s):  
Cancer Biology ◽  
Transforming Growth Factor ◽  
Biological Activities ◽  
Tumor Stroma ◽  
Transforming Growth Factor Β ◽  
Therapeutic Window ◽  
Annual Review ◽  
Publication Date ◽  
Tgfβ Signaling ◽  
Mesenchymal Transformation

Discovered 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. Expected final online publication date for the Annual Review of Cancer Biology, Volume 6 is April 2022. Please see http://www.annualreviews.org/page/journal/pubdates for revised estimates.

scholarly journals Ex Vivo Analysis of Primary Tumor Specimens for Evaluation of Cancer Therapeutics

2020 ◽  
Vol 5 (1) ◽  
Author(s):  
Cristina E. Tognon ◽  
Rosalie C. Sears ◽  
Gordon B. Mills ◽  
Joe W. Gray ◽  
Jeffrey W. Tyner
Keyword(s):  
Primary Tumor ◽  
Cancer Biology ◽  
Drug Sensitivity ◽  
Ex Vivo ◽  
Publication Date ◽  
Sensitivity Testing ◽  
Drug Activity ◽  
Drug Sensitivity Testing ◽  
Cancer Pathogenesis ◽  
Tumor Types

The use of ex vivo drug sensitivity testing to predict drug activity in individual patients has been actively explored for almost 50 years without delivering a generally useful predictive capability. However, extended failure should not be an indicator of futility. This is especially true in cancer research, where ultimate success is often preceded by less successful attempts. For example, both immune- and genetic-based targeted therapies for cancer underwent numerous failed attempts before biological understanding, improved targets, and optimized drug development matured to facilitate an arsenal of transformational drugs. Similarly, directly assessing drug sensitivity of primary tumor biopsies—and the use of this information to help direct therapeutic approaches—has a long history with a definitive learning curve. In this review, we survey the history of ex vivo testing and the current state of the art for this field. We present an update on methodologies and approaches, describe the use of these technologies to test cutting-edge drug classes, and describe an increasingly nuanced understanding of tumor types and models for which this strategy is most likely to succeed. We consider the relative strengths and weaknesses of predicting drug activity across the broad biological context of cancer patients and tumor types. This includes an analysis of the potential for ex vivo drug sensitivity testing to accurately predict drug activity within each of the biological hallmarks of cancer pathogenesis. Expected final online publication date for the Annual Review of Cancer Biology, Volume 5 is March 4, 2021. Please see http://www.annualreviews.org/page/journal/pubdates for revised estimates.

The Basis of Navigation Across Species

2021 ◽  
Vol 73 (1) ◽  
Author(s):  
Cody A. Freas ◽  
Ken Cheng
Keyword(s):  
Large Scale ◽  
Error Reduction ◽  
Annual Review ◽  
Publication Date ◽  
Additional Component ◽  
Oscillatory Systems ◽  
Neural Architecture ◽  
Wide Range ◽  
Reduction Strategies ◽  
Cycling Behavior

Animals navigate a wide range of distances, from a few millimeters to globe-spanning journeys of thousands of kilometers. Despite this array of navigational challenges, similar principles underlie these behaviors across species. Here, we focus on the navigational strategies and supporting mechanisms in four well-known systems: the large-scale migratory behaviors of sea turtles and lepidopterans as well as navigation on a smaller scale by rats and solitarily foraging ants. In lepidopterans, rats, and ants we also discuss the current understanding of the neural architecture which supports navigation. The orientation and navigational behaviors of these animals are defined in terms of behavioral error-reduction strategies reliant on multiple goal-directed servomechanisms. We conclude by proposing to incorporate an additional component into this system: the observation that servomechanisms operate on oscillatory systems of cycling behavior. These oscillators and servomechanisms comprise the basis for directed orientation and navigational behaviors. Expected final online publication date for the Annual Review of Psychology, Volume 73 is January 2022. Please see http://www.annualreviews.org/page/journal/pubdates for revised estimates.

Targeting KRAS G12C with Covalent Inhibitors

2021 ◽  
Vol 6 (1) ◽  
Author(s):  
Jonathan M.L. Ostrem ◽  
Kevan M. Shokat
Keyword(s):  
Clinical Trials ◽  
Cancer Biology ◽  
Phase Iii ◽  
Annual Review ◽  
Publication Date ◽  
Kras Mutations ◽  
Phase Iii Clinical Trials ◽  
Covalent Inhibitors ◽  
Novel Approaches ◽  
Early Phase Clinical Trials

KRAS 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. Expected final online publication date for the Annual Review of Cancer Biology, Volume 6 is April 2022. Please see http://www.annualreviews.org/page/journal/pubdates for revised estimates.

Engineering Advances in Spray Drying for Pharmaceuticals

2021 ◽  
Vol 12 (1) ◽  
Author(s):  
John M. Baumann ◽  
Molly S. Adam ◽  
Joel D. Wood
Keyword(s):  
Spray Drying ◽  
Oral Delivery ◽  
Process Development ◽  
Solid Dispersions ◽  
Amorphous Solid ◽  
Annual Review ◽  
Publication Date ◽  
Dry Powders ◽  
Wide Range ◽  
Pharmaceutical Industries

Spray drying is a versatile technology that has been applied widely in the chemical, food, and, most recently, pharmaceutical industries. This review focuses on engineering advances and the most significant applications of spray drying for pharmaceuticals. An in-depth view of the process and its use is provided for amorphous solid dispersions, a major, growing drug-delivery approach. Enhanced understanding of the relationship of spray-drying process parameters to final product quality attributes has made robust product development possible to address a wide range of pharmaceutical problem statements. Formulation and process optimization have leveraged the knowledge gained as the technology has matured, enabling improved process development from early feasibility screening through commercial applications. Spray drying's use for approved small-molecule oral products is highlighted, as are emerging applications specific to delivery of biologics and non-oral delivery of dry powders. Based on the changing landscape of the industry, significant future opportunities exist for pharmaceutical spray drying. Expected final online publication date for the Annual Review of Chemical and Biomolecular Engineering, Volume 12 is June 2021. Please see http://www.annualreviews.org/page/journal/pubdates for revised estimates.

The Coevolution of Placentation and Cancer

2021 ◽  
Vol 10 (1) ◽  
Author(s):  
Günter P. Wagner ◽  
Kshitiz ◽  
Anasuya Dighe ◽  
Andre Levchenko
Keyword(s):  
Twentieth Century ◽  
Cancer Cells ◽  
Immune Evasion ◽  
Online Publication ◽  
Cancer Biology ◽  
Annual Review ◽  
Publication Date ◽  
Trophoblast Cells ◽  
Cancer Hallmarks ◽  
Placental Invasion

Analogies between placentation, in particular the behavior of trophoblast cells, and cancer have been noted since the beginning of the twentieth century. To what degree these can be explained as a consequence of the evolution of placentation has been unclear. In this review, we conclude that many similarities between trophoblast and cancer cells are shared with other, phylogenetically older processes than placentation. The best candidates for cancer hallmarks that can be explained by the evolution of eutherian placenta are mechanisms of immune evasion. Another dimension of the maternal accommodation of the placenta with an impact on cancer malignancy is the evolution of endometrial invasibility. Species with lower degrees of placental invasion tend to have lower vulnerability to cancer malignancy. We finally identify several areas in which one could expect to see coevolutionary changes in placental and cancer biology but that, to our knowledge, have not been explored. Expected final online publication date for the Annual Review of Animal Biosciences, Volume 10 is February 2022. Please see http://www.annualreviews.org/page/journal/pubdates for revised estimates.

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