Cancer microenvironment articles within Nature Reviews Clinical Oncology

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  • Review Article |

    Dendritic cells (DCs) are antigen-presenting cells that function at the interface between innate and adaptive immunity, thereby acting as key mediators of antitumour immune responses and immunotherapy efficacy. In this Review, the authors outline the emerging complexity of intratumoural DC states that is being revealed through single-cell analyses as well as the contributions of different DC subsets to anticancer immunity and the activity of immune-checkpoint inhibitors. The authors also discuss advances in the development of DC-based cancer therapies and considerations for their potential combination with other anticancer therapies.

    • Ignacio Heras-Murillo
    • , Irene Adán-Barrientos
    •  & David Sancho

  • Review Article |

    Myeloid-derived suppressor cells (MDSCs) are a heterogeneous population of myeloid cells that accumulate in the tumour microenvironment, where they exert various immunosuppressive mechanisms as well as a variety of other tumour-promoting effects. Herein, the authors provide an overview of MDSC generation and their accumulation in tumours, describe the interplay between MDSCs and various other cell types found in tumours, and review the mechanisms by which MDSCs promote tumour development and progression, metastasis, and resistance to treatment. They also discuss the effects of established treatment modalities on MDSCs as well as implications for the development of novel therapeutic strategies targeting these cells.

    • Samantha A. Lasser
    • , Feyza G. Ozbay Kurt
    •  & Viktor Umansky

  • Review Article |

    Ovarian carcinoma is a highly heterogeneous tumour type, both spatially and temporally. As a consequence, these carcinomas are often associated with poor outcomes. Ovarian carcinoma comprises various subtypes with distinct complex molecular features. The authors of this Review discuss the molecular, cellular and anatomical heterogeneity of ovarian carcinoma, and outline the current and future treatment strategies for this malignancy.

    • Ana C. Veneziani
    • , Eduardo Gonzalez-Ochoa
    •  & Amit M. Oza

  • News & Views |

    Bispecific T cell engagers offer a novel treatment approach for patients with multiple myeloma, although mechanisms of resistance are largely unknown. Here, we discuss the implications of a recent report from Friedrich et al. that highlights the importance of pre-treatment T cell characteristics for a response to the T cell engager elranatamab and how these data might be used to inform future study and trial design.

    • Shonali Midha
    •  & Kenneth C. Anderson

  • Review Article |

    Emerging data indicate a central role for the microbiota in all aspects of colorectal cancer (CRC). Despite this general consensus, understanding the role of specific components of the microbiota in such a way that enables the development of clinical interventions or tools to inform clinical decision-making has thus far proved challenging. In this Review, the authors summarize the role of the microbiota in CRC, including in prevention, in interactions with treatment and as a source of novel biomarkers.

    • Chi Chun Wong
    •  & Jun Yu

  • Review Article |

    γδ T cells are lymphocytes with properties of both typical αβ T cell and natural killer cells, notable tissue tropisms, and MHC-independent antitumour functions that make them attractive agents for cancer immunotherapy. In this Review, the authors provide an overview of human γδ T cell subsets, discuss the antitumour and pro-tumour activities of these cells and their prognostic value in patients with cancer, and describe the current landscape of γδ T cell-based immunotherapies.

    • Sofia Mensurado
    • , Rafael Blanco-Domínguez
    •  & Bruno Silva-Santos

  • Review Article |

    The tumour microenvironment includes various diverse immune cell types, each of which might influence tumour progression and response to treatment, particularly with immunotherapies. These cell types include different subtypes of B lymphocytes, which are often associated with tertiary lymphoid structures (TLS) and can have pro-tumour or anti-tumour effects, either through their classical function in antibody production and antigen presentation or other mechanisms. Herein, Fridman et al. discuss the phenotypic heterogeneity of intratumoural B cells and the importance of TLS in their generation, the potential of B cells and TLS as prognostic and/or predictive biomarkers, and novel approaches aiming to enhance the development of TLS and anti-tumour B cells for cancer therapy.

    • Wolf H. Fridman
    • , Maxime Meylan
    •  & Catherine Sautès-Fridman

  • Review Article |

    The interaction of tumour-associated macrophages (TAMs) with cancer and stromal cells in the tumour microenvironment enables and sustains most of the hallmarks of cancer. The authors of this Review examine the diversity of TAMs in various cancer indications, which is being revisited with the advent of single-cell technologies, and discuss the functional roles of different TAM states, the prognostic and predictive value of TAM-related signatures as well as approaches involving TAMs that are currently being or will soon be tested in clinical trials.

    • Mikael J. Pittet
    • , Olivier Michielin
    •  & Denis Migliorini

  • Review Article |

    A variety of cytokines have diverse antitumour and/or pro-tumour activities and, accordingly, alterations in cytokine networks contribute to cancer development and progression. Therefore, cytokines and their receptors have long been investigated as therapeutic agents or targets in oncology, although with mostly disappointing results. Herein, Propper and Balkwill discuss the lessons learnt from initial clinical trials of monotherapy approaches as well as subsequent strategies to better leverage cytokines and cytokine antagonists in the treatment of solid tumours.

    • David J. Propper
    •  & Frances R. Balkwill

  • Review Article |

    Immunotherapy is revolutionizing the treatment of many cancers and hepatocellular carcinoma (HCC) is no exception. This Review describes the heterogeneous immune microenvironments of HCC as well as their links with the various aetiologies underlying this malignancy and with response or resistance to immunotherapies. In addition, the authors provide an overview of the current landscape of clinical trials evaluating immunotherapies across all stages of HCC.

    • Josep M. Llovet
    • , Florian Castet
    •  & Richard S. Finn

  • Review Article |

    Immune-checkpoint inhibitors have dramatically improved the outcomes in patients with advanced-stage cancers, although the majority of patients will not respond to these agents. Here, the authors describe the potential of targeting emerging immunomodulatory pathways, with a focus on alternative immune checkpoints and tumour metabolism as approaches that might enable further improvements in the outcomes of patients with cancer, either as monotherapies or in combination with existing agents.

    • Lukas Kraehenbuehl
    • , Chien-Huan Weng
    •  & Taha Merghoub

  • News & Views |

    Two recent studies addressed the functional properties and clinical significance of tumour antigen-specific effector T cells in human melanomas and lung carcinomas using single-cell strategies. Herein, we discuss their findings, which expand our understanding of T cell alterations in the tumour microenvironment and demonstrate that CD8+ T cell exhaustion is mediated by exposure to tumour cell-specific antigens and is associated with a tissue-resident memory phenotype.

    • Miguel Lopez de Rodas
    •  & Kurt A. Schalper

  • Review Article |

    Cancer-associated fibroblasts (CAFs) are inherently linked with cancers and have long been considered attractive therapeutic targets. However, the existence of several CAF subpopulations with substantial phenotypic and functional heterogeneity and plasticity is increasingly recognized. This Review provides an overview of the heterogeneity of CAFs and its implications with regard to the tumour-promoting and tumour-restraining roles of these cells as well as their clinical relevance in terms of prognostic value and therapeutic potential. The authors also provide insights and perspectives on future research and clinical studies involving CAFs.

    • Yang Chen
    • , Kathleen M. McAndrews
    •  & Raghu Kalluri

  • Review Article |

    Hypoxia is a common feature of tumours, contributes to many of the hallmarks of cancer and influences responses to anticancer therapies. Thus, strategies to eliminate and/or exploit tumour hypoxia have long been explored, although with limited success to date. Herein, the authors describe new insights into hypoxia biology, discuss the implications of these advances for novel hypoxia-directed therapeutic strategies, and review the progress made with longstanding methods for targeting hypoxic tumours.

    • Dean C. Singleton
    • , Andrew Macann
    •  & William R. Wilson

  • Review Article |

    The blood–brain barrier regulates the movement of various substances between the blood and the brain and therefore has a crucial role in ensuring normal brain function. In both primary brain tumours and brain metastases, the blood–brain barrier is modified to the blood–tumour barrier (BTB), resulting in altered permeability; however, the BTB continues to restrict the penetration of many therapeutic agents into intracranial tumours. Here, Patricia Steeg describes the current knowledge of BTB structure and function and discusses how this knowledge can be translated into improvements in cancer therapy and patient outcomes.

    • Patricia S. Steeg

  • Perspective |

    Patients with primary central nervous system (CNS) malignancies largely do not derive benefit from immune-checkpoint inhibitors. Paradoxically, a subset of those with CNS metastases from tumours located outside of the CNS will respond to the same approach. In this Perspective, the authors explore the key differences in the immune cell composition of primary CNS malignancies and brain metastases and provide guidance on potential alternative immunotherapies that might be effective in patients with these historically difficult-to-treat malignancies.

    • Martina Ott
    • , Robert M. Prins
    •  & Amy B. Heimberger

  • Review Article |

    Various cancers can disseminate to the bone, including the most common malignancies in men and women, prostate and breast cancer, respectively. Herein, the authors review the roles of the bone microenvironment in skeletal metastasis, highlighting the biology and clinical relevance of circulating tumour cells and disseminated tumour cells. Notably, bone metastases are associated with considerable morbidity and a poor prognosis, and the authors also discuss established and future therapeutic approaches for targeting components of the bone microenvironment to prevent or treat skeletal metastases.

    • Lorenz C. Hofbauer
    • , Aline Bozec
    •  & Klaus Pantel

  • Review Article |

    Signalling induced by extracellular adenosine (eADO) can suppress antitumour immunity through multiple mechanisms. Herein, the authors review the pathophysiological functions of eADO in cancer and the related prognostic implications. They discuss the associated opportunities for eADO pathway-targeted immunotherapy, highlighting potential limitations and the scope for combination and biomarker-based strategies. The data emerging from oncology clinical trials of the diverse range of therapies that have been developed to target the eADO signalling pathway are also described.

    • Bertrand Allard
    • , David Allard
    •  & John Stagg

  • Review Article |

    Important research efforts are being made to develop therapeutic strategies targeting the tumour microenvironment in pancreatic adenocarcinoma. The authors of this Review describe the apparent contradiction between preclinical studies and clinical outcomes observed to date, presenting more sophisticated strategies under active investigation.

    • Won Jin Ho
    • , Elizabeth M. Jaffee
    •  & Lei Zheng

  • News & Views |

    Effective anticancer therapies typically activate antitumour immunity, predominately mediated by T cells in the tumour microenvironment. Here, we discuss the roles of B cells and tertiary lymphoid structures in the context of chemotherapy-induced complement activation, which results in the induction of a B cell subset that modulates T cell function.

    • Catherine Sautès-Fridman
    •  & Lubka T. Roumenina

  • Review Article |

    Virtually all patients with resectable pancreatic ductal adenocarcinoma (PDAC) will have disease progression, which is generally associated with dismal outcomes. However, novel targeted therapies and immunotherapies, selected based on the genomic and/or clinical features of patients’ tumours are beginning to improve the outcomes in subsets of patients. In this Review, the authors describe progress in novel therapies for patients with PDAC.

    • Christopher Nevala-Plagemann
    • , Manuel Hidalgo
    •  & Ignacio Garrido-Laguna

  • Review Article |

    Oncolytic viruses are beginning to enter clinical use in patients with cancer despite regulatory and practical considerations precluding the widespread use of such therapies. Here, the authors describe the potential of non-viral methods in achieving oncolytic effects and how these effects might prime the development of antitumour immune responses in patients with cancer.

    • Oliver Kepp
    • , Aurelien Marabelle
    •  & Guido Kroemer

  • News & Views |

    Glioblastoma remains essentially incurable, and new therapeutic approaches are urgently needed. Now, the findings of three serial tissue-based studies suggest that immune-checkpoint inhibition can modify the glioblastoma microenvironment. Following these encouraging observations, the results of two phase III trials of immune-checkpoint inhibition in newly diagnosed glioblastoma, with larger cohorts of patients, are eagerly anticipated.

    • Michael Weller
    •  & Emilie Le Rhun

  • Review Article |

    The development of more-targeted cancer therapies has not been matched by more-targeted imaging methods. This discrepancy has, in some scenarios, resulted in inaccurate assessments of the effects of novel therapies. In this Review, the authors describe potential novel imaging approaches that could be adopted to enable improvements in imaging-based monitoring of treatment responses and resistance.

    • Mirjam Gerwing
    • , Ken Herrmann
    •  & Moritz Wildgruber

  • Review Article |

    Regulatory T (Treg) cells are implicated in cancer immune evasion and escape and thus contribute to tumour development and progression. In this Review, the authors provide an overview of the phenotypes and roles of Treg cells in the context of cancer and outline potential strategies to target this cell type in anticancer immunotherapy.

    • Yosuke Togashi
    • , Kohei Shitara
    •  & Hiroyoshi Nishikawa

  • Review Article |

    The mechanisms of resistance to immunotherapy seem to broadly overlap with the immunoediting process whereby cancers evade detection by the immune system. The authors of this Review discuss these interactions as well as the strategies that can be used to overcome therapeutic resistance

    • Jake S. O’Donnell
    • , Michele W. L. Teng
    •  & Mark J. Smyth

  • Review Article |

    Intriguing evidence suggests that expression of RANK or RANKL by various cells of the tumour microenvironment modulates the anticancer immune response. Herein, the authors review this evidence, discuss the current preclinical and clinical data supporting a potential of RANKL inhibition to improve anticancer immunotherapy and describe hypothetical immune-related mechanisms of action.

    • Elizabeth Ahern
    • , Mark J. Smyth
    •  & Michele W. L. Teng

  • Review Article |

    Emerging evidence indicates that tumour-derived extracellular vesicles (EVs), notably exosomes, mediate intercellular communication to promote cancer development and progression. Herein, the authors discuss EV properties and physiological functions, particularly their pro-metastatic effects, and highlight the diagnostic and therapeutic potential of EVs in cancer.

    • Rong Xu
    • , Alin Rai
    •  & Richard J. Simpson

  • Review Article |

    The tumour stroma is a component of the tumour microenvironment and has crucial roles in tumour initiation, progression, and metastasis. Most anticancer therapies target cancer cells specifically, but the tumour stroma can promote resistance to such therapies. Herein, the authors provide an overview of the complex cancer cell–tumour stroma interactions and discuss how novel treatment strategies should combine anticancer and antistromal agents.

    • Kenneth C. Valkenburg
    • , Amber E. de Groot
    •  & Kenneth J. Pienta

  • Review Article |

    Glioblastoma is a disease associated with a dismal patient prognosis, necessitating the development of novel therapies. Substantial research effort is being devoted to the development of immunotherapies for glioblastoma. Herein, the rationale and promise for this approach are discussed, together with the challenges and how they might be overcome.

    • Michael Lim
    • , Yuanxuan Xia
    •  & Michael Weller

  • Review Article |

    The combination of immunotherapies with other therapeutic modalities, including anti-angiogenic agents, is currently under investigation to improve the outcomes of patients receiving immunotherapies. In this article, the authors review the effects mediated by anti-angiogenic agents that might increase the efficacy of immunotherapies and discuss the possibility that immunotherapies might increase the efficacy of anti-angiogenic agents and/or promote changes in the tumour vasculature.

    • Kabir A. Khan
    •  & Robert S. Kerbel

  • Review Article |

    Both multiple myeloma and acute myeloid leukaemia are often preceded by defined precursor stages of neoplasia, which can aid efforts to unravel the mechanisms of disease progression. Herein, the authors review studies of the important roles of microenvironmental factors in promoting the development and progression of haematological cancers in these precursor conditions. Potential therapeutic strategies targeting the abnormal bone-marrow microenvironment are discussed.

    • Irene M. Ghobrial
    • , Alexandre Detappe
    •  & David P. Steensma

  • Research Highlight |

    • Diana Romero

  • Comment |

    Few clinical trials incorporate studies of evolutionary cancer biology, despite the frequent emergence of acquired resistance to anticancer therapies. This problem motivated the first CRUK Marshall Symposium on Cancer Evolution in May 2017, which provided a forum for evolutionary and ecological theorists, cancer biologists, and clinicians to consider how evolutionary biology might inform improvements in cancer medicine. Herein, we discuss the key themes and opportunities for the future.

    • Erik Sahai
    •  & Charles Swanton

  • Review Article |

    Virtually all successful treatments of cancer either create, restore or enhance the antitumour immune response. Therefore, the specific features of the immune microenvironment, both before and after treatment, are important determinants of patients' outcomes. In this Review, the authors describe the influence of the immunological characteristics of the tumour microenvironment on responses to treatment in patients with a variety of cancers.

    • Wolf H. Fridman
    • , Laurence Zitvogel
    •  & Guido Kroemer

  • Comment |

    Patients with resectable solid tumours can harbour minimal residual disease (MRD) after initial treatment, which is a potential source for subsequent metastatic relapse. The interaction between disseminated tumour cells (DTCs) and the new microenvironment in which they reside determines whether DTCs remain dormant or progress into overt metastases. We highlight the promise of liquid biopsies to inform on MRD.

    • Klaus Pantel
    •  & Catherine Alix-Panabières

  • Review Article |

    Tumour-associated macrophages (TAMs) are key drivers of tumour-promoting inflammation and cancer progression, and are important determinants of responsiveness to a range of therapies. Herein, the authors summarize the roles of TAMs in cancer, and discuss the potential of TAM-targeted therapeutic strategies to complement and synergize with other anticancer treatments.

    • Alberto Mantovani
    • , Federica Marchesi
    •  & Paola Allavena

  • Review Article |

    The interaction between radiotherapy and the host immune system has uncovered new mechanisms that can be exploited to improve the efficacy of radiotherapy. In this article, the authors highlight data providing new explanations for the success or failure of radiotherapy, and postulate, using radiation-induced tumour equilibrium (RITE) as an example, how the combination of immune-modulation and radiation could tip the balance of the host immune response to promote cure.

    • Ralph R. Weichselbaum
    • , Hua Liang
    •  & Yang-Xin Fu

  • Review Article |

    To form metastases, cancer cells must leave the immunosuppressive tumour microenvironment and traffic, predominantly in the circulation, to new tissue sites, where they must then expand. During this process, the tumour cells are open to attack by the immune system. This Review highlights the possible mechanisms used by circulating tumour cells in the blood and disseminated tumour cells in other tissues to evade, escape, or subvert the immune system in order to survive and form metastatic lesions.

    • Malte Mohme
    • , Sabine Riethdorf
    •  & Klaus Pantel

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