Immunology articles within Nature Reviews Clinical Oncology

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  • Review Article |

    Following their successful implementation in the COVID-19 pandemic, the technology behind mRNA vaccines is now being applied to cancer. In this Review, the authors described the several decades of development of mRNA vaccines for patients with cancer, including initial developments in this area involving cell-based vaccines as well as more recent developments with nanoparticle-encapsulated vaccines, which are beginning to show promising clinical activity.

    • Elias J. Sayour
    • , David Boczkowski
    •  & Smita K. Nair

  • 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 |

    Identifying patients who are likely to benefit from immune-checkpoint inhibitors remains one of the major challenges in immunotherapy. Cancer immunogenomics is an emerging field that bridges genomics and immunology. The authors of this Review provide an overview of the computational approaches currently available to analyse bulk tissue and single-cell sequencing data from cancer, stromal and immune cells.

    • Venkateswar Addala
    • , Felicity Newell
    •  & Nicola Waddell

  • Review Article |

    The availability of regimens containing one or more immune-checkpoint inhibitors (ICIs) has improved the outcomes in patients with advanced-stage hepatocellular carcinoma. However, clinical benefit from these regimens is difficult to predict, indicating the need for novel biomarkers. In this Review, the authors describe the available evidence on biomarkers to guide the use of ICIs in these patients and discuss promising future research directions.

    • Tim F. Greten
    • , Augusto Villanueva
    •  & Xin W. Wang

  • Review Article |

    Several trials are testing immune-checkpoint inhibitors (ICIs), alone or in combination with chemotherapy, in patients with resectable non-small-cell lung cancer as an adjuvant, neoadjuvant or perioperative approach. However, the optimal use of ICIs with curative intent in patients with early stage non-small-cell lung cancer remains unclear. The authors of this Review discuss the current trial landscape and discuss challenges and opportunities.

    • Giannis Mountzios
    • , Jordi Remon
    •  & Solange Peters

  • 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

  • Review Article |

    Chimeric antigen receptor (CAR) T cells have dramatically improved the outcomes of patients with certain relapsed and/or refractory haematological malignancies. Owing to the promising short-term survival outcomes achieved, long-term data on both safety and survival are becoming increasingly relevant. In this Review, the authors describe the available long-term follow-up data from early studies testing the safety and efficacy of receiving CAR T cells targeting CD19 as well as more recent data on BCMA-targeted CAR T cells in patients with relapsed and/or refractory multiple myeloma.

    • Kathryn M. Cappell
    •  & James N. Kochenderfer

  • 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 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 |

    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 |

    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

  • Review Article |

    Chimeric antigen receptor (CAR) T cell therapies are generating substantial excitement and have been approved for the treatment of various haematological malignancies. All approved CARs consist of an extracellular antigen-binding domain linked to an intracellular region containing a costimulatory domain and a T cell activation domain. A key question is whether the CD28-derived and 4-1BB-derived costimulatory domains used in current commercial CAR T cell products are associated with different cellular and clinical effects. Herein, Cappell and Kochenderfer provide an overview of CD28 and 4-1BB costimulatory pathways and compare the outcomes observed in preclinical and clinical studies with CARs incorporating either costimulatory domain.

    • Kathryn M. Cappell
    •  & James N. Kochenderfer

  • Review Article |

    Limited penetration into tumour tissue can restrict the activity of systemically delivered cancer immunotherapies, whereas exposure of various non-malignant tissues to high levels of such agents can lead to problematic toxicities. Intratumoural administration and/or biotechnology strategies for selective targeting of tumour tissues have the potential to circumvent these issues and thereby increase the therapeutic index. Herein, the authors review the historical origins and current landscape of intratumoural and tumour tissue-targeted immunotherapies.

    • Ignacio Melero
    • , Eduardo Castanon
    •  & Aurelien Marabelle

  • 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

  • Perspective |

    Anti-angiogenic therapy has the capacity to ameliorate antitumour immunity and, thus, some combinations of anti-angiogenics and immunotherapies have been approved and a number of them are being tested. The authors of this Perspective describe how the angiogenesis-induced endothelial immune cell barrier hampers antitumour immunity and the role of endothelial cell anergy as a vascular counterpart of immune checkpoints.

    • Zowi R. Huinen
    • , Elisabeth J. M. Huijbers
    •  & Arjan W. Griffioen

  • News & Views |

    Talimogene laherparepvec (T-VEC) is an oncolytic virus approved for the treatment of patients with recurrent melanoma. Now, a recent study in patients with primary cutaneous B cell lymphoma confirms prior results in melanoma and reveals new mechanisms of action. Herein, we discuss these findings and their implications for expanding the role of oncolytic viruses.

    • Howard L. Kaufman
    •  & Dawid Maciorowski

  • 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 |

    The treatment of immune-related adverse events (irAEs) in patients receiving immune checkpoint inhibitors has mostly been based on adapting therapeutic approaches used in the management of primary autoimmune diseases. The authors of this Review provide an overview of the different cellular and soluble immune factors involved in the pathogenesis of irAEs in order to help clinicians deliver personalized immunopathologically guided treatment to manage these adverse events.

    • Khashayar Esfahani
    • , Arielle Elkrief
    •  & Leonard Calabrese

  • News & Views |

    Liu et al. report data from the largest sequencing analysis of tumour material from patients with metastatic melanoma receiving immune-checkpoint inhibitors. These data confirm the correlations between baseline immune infiltrate and treatment response, but also demonstrate inconsistent associations of tumour mutational burden, specific gene mutations and previously described gene expression patterns with clinical outcomes.

    • Jason J. Luke
    •  & Paolo A. Ascierto

  • Review Article |

    Neutrophils accumulate in the circulation of patients with cancer, and the neutrophil-to-lymphocyte ratio is a widely used biomarker. However, the effects of neutrophils on tumour development and progression, and the efficacy of therapies, remain relatively unknown. In this Review, the authors draw on data from animal models and patients with cancer to provide an overview of the effects of neutrophils in cancer.

    • Merav E. Shaul
    •  & Zvi G. Fridlender

  • News & Views |

    Inhibition of the NKG2A immune checkpoint restores natural killer cell and T cell effector function in preclinical cancer models. In addition, NKG2A blockade in combination with other therapeutic antibodies is showing encouraging responses in a subset of patients with metastatic colorectal or head and neck cancer. However, established biomarkers of response are lacking, and larger trials are needed to enable firm conclusions to be drawn about whether NKG2A inhibition complements existing immunotherapies.

    • Benjamin C. Creelan
    •  & Scott J. Antonia

  • Review Article |

    A deterioration of disease can occur upon treatment with anti-PD-1/PD-L1 monoclonal antibodies; this paradoxical phenomenon is defined as hyperprogression. The authors discuss the pathophysiological hypotheses that might explain hyperprogressive disease and the resulting challenges for patient management, with a focus in clinical decisions involving immune-checkpoint inhibitors.

    • Stéphane Champiat
    • , Roberto Ferrara
    •  & Charles Ferté

  • Review Article |

    The interleukin-6 (IL-6)/Janus kinase (JAK)/signal transducer and activator of transcription 3 (STAT3) pathway is aberrantly hyperactivated in many types of cancer, and such hyperactivation is generally associated with a poor clinical prognosis. In this Review, the authors describe the clinical potential of agents designed to inhibit the IL-6/JAK/STAT3 signalling pathway, either alone or in combination with other agents, in patients with cancer.

    • Daniel E. Johnson
    • , Rachel A. O'Keefe
    •  & Jennifer R. Grandis

  • Review Article |

    The development of predictive biomarkers is complex and the non-systematic approach to biomarker development in HER2-positive breast cancer challenges the way translational research is performed. Women with very favourable prognostic features will likely prefer shorter courses of treatment and might enquire about the possibility to forego aggressive chemotherapy. Considering these legitimate needs, Gingras et al. review the results of more than a decade of translational research efforts in this disease.

    • Isabelle Gingras
    • , Géraldine Gebhart
    •  & Martine Piccart-Gebhart

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