Tumour immunology articles within Nature Reviews Clinical Oncology

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  • Perspective |

    The benefit of combining antiangiogenic agents with immune-checkpoint inhibitors has been demonstrated in pivotal phase III trials across different cancer types, some with practice-changing results; however, other phase III trials have had negative results. The authors of this Perspective discuss the variable outcomes of these trials, considering factors that account for these differences and suggesting future initiatives for improving the outcomes in patients receiving these combinations.

    • Hung-Yang Kuo
    • , Kabir A. Khan
    •  & Robert S. Kerbel

  • Review Article |

    Increasing evidence indicates that signalling networks activated downstream of oncogenic alterations contribute fundamentally to cancer immune evasion, including by promoting the accumulation of regulatory T (Treg) cells and other immunosuppressive cells in the tumour microenvironment (TME). Herein, the authors discuss the mechanisms via which cancers engage Treg cells to evade antitumour immunity, as well as the characteristics of Treg cells in the TME and their roles in resistance to immune-checkpoint inhibitors. Considering these aspects, they propose the concept of ‘immuno-genomic cancer evolution’ for tumorigenesis and the related paradigm of ‘immuno-genomic precision medicine’, postulating that the specific characteristics of cancer, especially genetic profiles that correlate with particular immunosuppressive networks in the TME, are likely to inform individualized strategies for combining molecularly targeted agents with immunotherapies.

    • Shogo Kumagai
    • , Kota Itahashi
    •  & Hiroyoshi Nishikawa

  • 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

  • News & Views |

    Several novel personalized therapies focus on targeting neoantigens. Such strategies require the identification of suitable vaccine neoepitopes or neoantigen-specific T cell receptor (TCR) clonotypes. Herein, we discuss a recently published report that describes a combined transcriptional and phenotype signature, NeoTCRPBL, that enables the minimally invasive identification of rare neoantigen-specific TCRs from peripheral blood that might enable more-effective T cell-based therapies against cancer.

    • Marco Donia
    •  & Inge Marie Svane

  • Review Article |

    Antibody–drug conjugates (ADCs) are effective cancer drugs that have been approved for more than 20 specific indications. Nonetheless, acquired resistance and adverse events both limit the effectiveness of these agents. In this Review, the authors describe the development of novel ADC designs, including bispecific ADCs, probody–drug conjugates, immune-stimulating ADCs, protein-degrader ADCs and dual-drug ADCs. all of which have the potential to address these challenges and provide more effective ADCs.

    • Kyoji Tsuchikama
    • , Yasuaki Anami
    •  & Chisato M. Yamazaki

  • 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 |

    Immune-checkpoint inhibitors (ICIs) and other immunotherapies have revolutionized the treatment of patients with cancer. Nonetheless, most patients do not derive durable benefit, indicating a need for biomarkers to guide treatment selection. In this Review, the authors describe the role of antigen presentation in response to ICIs and other immunotherapies, with a focus on the role of molecular and/or genomic alterations affecting antigen presentation.

    • Kailin Yang
    • , Ahmed Halima
    •  & Timothy A. Chan

  • Review Article |

    Radiotherapy has several key attributes that make it an attractive combination partner for immunotherapy; however, numerous clinical trials investigating the combination of these two treatment modalities have failed to demonstrate clear improvements in patient outcomes. In this Review, Galluzzi and colleagues discuss the evidence indicating that radiotherapy administered according to standard schedules and target volumes might impair immune fitness and, therefore, propose that adaptation of the radiotherapy regimens to immunotherapy (and not vice versa) might synergistically enhance the antitumour immune response to achieve meaningful clinical benefits.

    • Lorenzo Galluzzi
    • , Molykutty J. Aryankalayil
    •  & Silvia C. Formenti

  • 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 |

    Neoadjuvant immune-checkpoint inhibition is a promising emerging treatment strategy that potentially enables patients with a good response to initial therapy to avoid further treatment and the associated toxicity risks, while also identifying those who might require treatment escalation. In this Review, the authors describe treatment personalization strategies based on the initial response to one or more neoadjuvant immune-checkpoint inhibitors and consider the potential to expand this approach beyond patients with melanoma.

    • Minke W. Lucas
    • , Judith M. Versluis
    •  & Christian U. Blank

  • 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 |

    Chimeric antigen receptor (CAR) T cells are effective therapies for patients with relapsed and/or refractory B cell malignancies, partly owing to the ability to target B cell-specific antigens. However, CAR T cells targeting solid tumour antigens are likely to carry a higher risk of on-target, off-tumour toxicity (OTOT). Here, the authors summarize the available data on OTOT in the context of CAR T cells targeting solid tumour antigens and describe novel CAR T cell designs that might overcome such toxicities.

    • Christian L. Flugel
    • , Robbie G. Majzner
    •  & Mohamed Abou-el-Enein

  • Review Article |

    T cells are key effectors of immunotherapies that have revolutionized the treatment of cancer; however, chronic exposure to tumour-associated antigens can result in progressive loss of T cell effector functions and self-renewal capacity, a state termed ‘T cell exhaustion’ that is believed to limit the efficacy of immunotherapy. This Review synthesizes the new immunobiological insights that present a more nuanced view beyond T cell exhaustion being entirely undesirable and indicate that this hypofunctional state might be as much a reflection as it is the cause of poor tumour control. Hence, the authors describe how, in certain contexts, interruption of this programme could impair T cell persistence and discuss interventions to mitigate the development of T cell exhaustion that might ultimately improve clinical outcomes.

    • Andrew Chow
    • , Karlo Perica
    •  & Jedd D. Wolchok

  • 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 |

    Antibodies targeting PD-1 or its ligand PD-L1 have revolutionized cancer therapy. Increased understanding of the mechanisms regulating PD-L1 has revealed links with several important oncogenic signalling pathways. Herein, the authors review the transcriptional, post-transcriptional and translational regulation of PD-L1 expression in cancers as well as the diverse post-translational modifications, including phosphorylation, palmitoylation, glycosylation, acetylation and ubiquitination, that affect PD-L1 stability and activity. They also discuss the possibility to simultaneously target key oncogenic pathways and modulate PD-L1 expression using small-molecule agents, which have potential advantages over or might synergize with anti-PD-1/PD-L1 antibodies.

    • Hirohito Yamaguchi
    • , Jung-Mao Hsu
    •  & Mien-Chie Hung

  • 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 |

    Targeted therapies have improved the outcomes of many patients with cancer, although many more lack targetable alterations or do not derive clinical benefit for other reasons. Radiotherapy can also provide benefit to many patients, although radioresistance often limits the effectiveness of this intervention. Here, the authors describe the potential for radiotherapy to promote non-oncogene dependence on targetable signalling pathways, thus extending the benefits of both targeted therapy and radiotherapy to greater numbers of patients.

    • Giulia Petroni
    • , Lewis C. Cantley
    •  & Lorenzo Galluzzi

  • 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 |

    In the past few years, advances in omics technologies have led to a better understanding of the heterogeneity of triple-negative breast cancers (TNBCs) and their microenvironment, supporting a view of this breast cancer subtype as an ecosystem that encompasses the intrinsic and extrinsic features of cancer cells. The authors of this Review describe the current and upcoming therapeutic landscape of TNBC and discuss how an integrated view of the TNBC ecosystem can provide improved opportunities for tailoring treatment.

    • Giampaolo Bianchini
    • , Carmine De Angelis
    •  & Luca Gianni

  • News & Views |

    Chimeric antigen receptor (CAR) T cells have remarkable efficacy in patients with B cell acute lymphoblastic leukaemia (ALL), but have not been successful to date in patients with T cell ALL (T-ALL). Now, data from Pan and colleagues demonstrate the safety and impressive short-term efficacy of allogeneic donor-derived anti-CD7 CAR T cells in an early-phase clinical trial involving patients with relapsed and/or refractory T-ALL.

    • David T. Teachey
    •  & Stephen P. Hunger

  • 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 |

    Despite being the most common primary bone cancer in children and young adults, osteosarcoma is a rare cancer, a fact that has complicated efforts to improve patient outcomes. Moreover, the molecular biology of disease is highly heterogeneous and most of the recurrent genetic alterations occur in tumour-suppressor genes that are challenging therapeutic targets. Herein, Gill and Gorlick discuss the new biological discoveries, technologies, and therapeutic agents and approaches that, through collaborative efforts, are poised to generate advances in the treatment of osteosarcoma after more than four decades of stagnation.

    • Jonathan Gill
    •  & Richard Gorlick

  • Perspective |

    Immune responses against tumour antigens that do not arise from cancer cell-specific mutations can result in autoimmune reactions against the tissue of origin of the tumour. Despite their undesirable effects, these symptoms can have prognostic value and correlate with favourable disease outcomes. The authors of this Perspective discuss the importance of such beneficial autoimmunity in patients with advanced-stage disease and in cancer immunosurveillance.

    • Laurence Zitvogel
    • , Claude Perreault
    •  & Guido Kroemer

  • News & Views |

    An unfavourable gut bacterial composition has been shown to reduce the likelihood of clinical benefit from immune-checkpoint inhibitors (ICIs). The results of two first-in-human studies of faecal microbiota transplantation in patients with melanoma refractory to anti-PD-1 antibodies validate preclinical evidence that this approach can improve the gut microbiota and overcome resistance to ICIs; however, many questions remain.

    • Arielle Elkrief
    •  & Bertrand Routy

  • Review Article |

    CD19-specific chimeric antigen (CAR)-modified T cells are approved for patients with advanced-stage forms of certain B cell malignancies. However, a subset of patients will have anti-CAR immune responses, leading to a lack of CAR T cell persistence and a rapid loss of any antitumour efficacy. In this Review, the authors describe the extent of anti-CAR immune responses in patients and suggest measures that could be used to better monitor for these events. Additionally, they describe novel approaches to CAR T cell therapy that might reduce the risk of such responses in the future.

    • Dimitrios L. Wagner
    • , Enrico Fritsche
    •  & Mohamed Abou-el-Enein

  • Review Article |

    Personalized neoantigen-based therapeutic vaccines hold promise as cancer immunotherapies. This Review provides an overview of the complex personalized neoantigen vaccine production process, vaccine-induced T cell responses and strategies to enhance these responses. Completed and ongoing clinical studies testing such vaccines are discussed, and considerations for future clinical investigation of this novel, individualized form of immunotherapy are outlined.

    • Eryn Blass
    •  & Patrick A. Ott

  • News & Views |

    Tumour-associated antigens are an attractive therapeutic target in immuno-oncology. Here, the exploratory analyses of T cell responses and preliminary clinical outcomes of the Lipo-MERIT trial of a melanoma vaccine are discussed in the context of prior efforts to harness the immunogenicity of such antigens for antitumour immunity.

    • Anjali Rohatgi
    •  & John M. Kirkwood

  • Review Article |

    Natural killer (NK) cells have an innate potential to kill cancerous cells and considerable effort is being focused on innovative approaches to leverage these cells for cancer therapy. Herein, the authors discuss the variety of NK cell-based therapies that are being developed for the treatment of diverse cancers and identify future avenues for NK cell therapy research.

    • Jacob A. Myers
    •  & Jeffrey S. Miller

  • Review Article |

    The efficacy of chemotherapy in patients with cancer is now known to have an immunogenic component. Nonetheless, chemotherapy alone often fails to provide durable disease remission in most patients. The development of immune checkpoint inhibitors has created an opportunity to combine immunogenic chemotherapies with these agents in order to optimize patient outcomes. In this Review, the authors describe the mechanisms of synergy between chemotherapy and immune checkpoint inhibitors, summarize the available clinical data on these effects and highlight the most promising areas for future research.

    • Lorenzo Galluzzi
    • , Juliette Humeau
    •  & Guido Kroemer

  • Review Article |

    Immune-checkpoint inhibition has transformed the treatment of patients with advanced-stage cancers. Nonetheless, the specific antigens targeted by T cells that are activated or reactivated by these agents remain largely unknown. In this Review, the authors describe the characterization and classification of tumour antigens including descriptions of the most appropriate detection methods, and discuss potential regulatory issues regarding the use of tumour antigen-based therapeutics.

    • Sebastian P. Haen
    • , Markus W. Löffler
    •  & Peter Brossart

  • 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

  • Perspective |

    Surgery remains a key pillar of cancer therapy, particular for those with curable, localized disease. The immediate perioperative period (days before and after surgery) is associated with various psychological and physiological stresses and associated factors, including inflammatory mediators, that might promote cancer progression and thus determine long-term outcomes. Herein, the authors present the hypothesis and supporting evidence that the use of certain types of immunotherapy, together with interventions to abrogate stress–inflammatory responses, in conjunction with surgery might improve the overall success of cancer treatment.

    • Pini Matzner
    • , Elad Sandbank
    •  & Shamgar Ben-Eliyahu

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