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Key Points Adoptive immunotherapy has rapidly evolved to harness modern genetic techniques to create T cells with enhanced specificity, efficacy and safety. Artificial expression of chimeric antigen receptors (CARs) or engineered T cell receptors (TCRs) in autologous T cells has enabled a new generation of targeted cellular therapeutics. Early clinical trials targeting B cell malignancies have shown great promise, generating unprecedented response rates to treatment of patients with relapsed and refractory B cell acute lymphoblastic leukaemia (B-ALL). As more patients with different B cell malignancies are treated, areas for further optimization are brought to light. Engineered T cell therapy has been adapted to treat non-B cell malignancies, including multiple myeloma and myeloid malignancies as well as solid tumours. To date, target selection has proved challenging as many tumour-conserved markers are also expressed on benign tissues (for example, mesothelin) and other tumour-specific markers are less uniformly expressed (for example, epidermal growth factor receptor variant III (EGFRvIII)). More precise targeting of tumour cell subsets, such as cancer stem cells, or targeting of portions of intracellular tumour markers in the context of the major histocompatibility complex (MHC), may enhance specificity and limit off-tumour effects. Combining non-specific and specific immune responses (for example, T cells redirected for universal cytokine killing (TRUCKs), fluorescein isothiocyanate (FITC)–folate plus FITC-CAR T cell) could further enhance antitumour immune response, while minimizing off-tumour effects. Although lentiviral and retroviral transduction are still the most common approaches to ex vivo T cell gene modification, DNA and RNA transfection have some advantages. In particular, RNA transfection of short guide RNAs enables CRISPR–Cas9 modification of T cells. This targeted gene disruption approach could help to create engineered T cells with supraphysiological antitumour capabilities. In addition to specificity-enhancing artificial receptor expression, the next generation of engineered T cells may include modifications to overcome tumour-mediated immune suppression, additional receptors to enable Boolean gating of signal transduction or safety switches to enhance precision control of in vivo engineered T cell activity. This Review assesses what we have learnt about adoptive cell transfer of engineered T cells for the treatment of patients with B cell malignancies and discusses how this therapy can be improved and applied to other malignancies, including solid tumours. The immune system evolved to distinguish non-self from self to protect the organism. As cancer is derived from our own cells, immune responses to dysregulated cell growth present a unique challenge. This is compounded by mechanisms of immune evasion and immunosuppression that develop in the tumour microenvironment. The modern genetic toolbox enables the adoptive transfer of engineered T cells to create enhanced anticancer immune functions where natural cancer-specific immune responses have failed. Genetically engineered T cells, so-called 'living drugs', represent a new paradigm in anticancer therapy. Recent clinical trials using T cells engineered to express chimeric antigen receptors (CARs) or engineered T cell receptors (TCRs) have produced stunning results in patients with relapsed or refractory haematological malignancies. In this Review we describe some of the most recent and promising advances in engineered T cell therapy with a particular emphasis on what the next generation of T cell therapy is likely to entail.

Although immunotherapeutics targeting the inhibitory receptors (IRs) CTLA-4, PD-1 or PD-L1 have made substantial clinical progress in cancer, a considerable proportion of patients remain unresponsive to treatment. Targeting novel IR–ligand pathways in combination with current immunotherapies may improve clinical outcomes. New clinical immunotherapeutics target T cell–expressed IRs (LAG-3, TIM-3 and TIGIT) as well as inhibitory ligands in the B7 family (B7-H3, B7-H4 and B7-H5), although many of these targets have complex biologies and unclear mechanisms of action. With only modest clinical success in targeting these IRs, current immunotherapeutic design may not be optimal. This Review covers the biology of targeting novel IR–ligand pathways and the current clinical status of their immunotherapeutics, either as monotherapy or in combination with antibody to PD-1 or to its ligand PD-L1. Further understanding of the basic biology of these targets is imperative to the development of effective cancer immunotherapies. Checkpoint blockade has revolutionized cancer immunotherapy; however, this approach is effective in only a subset of cancers. In their Review, Vignali and colleagues discuss novel checkpoint targets and their biology and clinical potential.

Immunotherapy based on checkpoint inhibitors is providing substantial clinical benefit, but only to a minority of cancer patients. The current priority is to understand why the majority of patients fail to respond. Besides T-cell dysfunction, T-cell apoptosis was reported in several recent studies as a relevant mechanism of tumoral immune resistance. Several death receptors (Fas, DR3, DR4, DR5, TNFR1) can trigger apoptosis when activated by their respective ligands. In this review, we discuss the immunomodulatory role of the main death receptors and how these are shaping the tumor microenvironment, with a focus on Fas and its ligand. Fas-mediated apoptosis of T cells has long been known as a mechanism allowing the contraction of T-cell responses to prevent immunopathology, a phenomenon known as activation-induced cell death, which is triggered by induction of Fas ligand (FasL) expression on T cells themselves and qualifies as an immune checkpoint mechanism. Recent evidence indicates that other cells in the tumor microenvironment can express FasL and trigger apoptosis of tumor-infiltrating lymphocytes (TIL), including endothelial cells and myeloid-derived suppressor cells. The resulting disappearance of TIL prevents anti-tumor immunity and may in fact contribute to the absence of TIL that is typical of “cold” tumors that fail to respond to immunotherapy. Interfering with the Fas–FasL pathway in the tumor microenvironment has the potential to increase the efficacy of cancer immunotherapy.

Regulatory T cells (Tregs) play essential roles in immune homeostasis; however, their role in tumor microenvironment (TME) is not completely evident. Several studies reported that infiltration of Tregs into various tumor tissues promotes tumor progression by limiting antitumor immunity and supporting tumor immune evasion. Furthermore, in TME, Tregs include heterogeneous subsets of cells expressing different immunosuppressive molecules favoring tumor progression. For an effective cancer therapy, it is critical to understand the Treg heterogeneity and biology in the TME. Recent studies have shown that immune checkpoint molecules promote cancer progression through various antitumor inhibitory mechanisms. Recent advances in cancer immunotherapy have shown the promising potentials of immune checkpoint inhibitors (ICIs) in inducing antitumor immune responses and clinical benefits in patients with cancer at late stages. Most studies revealed the effect of ICIs on T effector cells, and little is known about their effect on Tregs. In this review, we highlight the effects of the ICIs, including anti‐CTLA‐4, anti‐PD‐1/PD‐L1, anti‐LAG‐3, anti‐TIM‐3, and anti‐TIGIT, on tumor‐infiltrating and peripheral Tregs to elicit effector T‐cell functions against tumors. Additionally, we discuss how ICIs may target Tregs for cancer immunotherapy. Recent advances confirmed the key roles of the immune checkpoints in tumor progression, and their blockade showed promising potentials in cancer therapy. This review highlights the effect of immune checkpoint inhibitors, including anti‐CTLA‐4, anti‐PD‐1/PD‐L1, anti‐LAG‐3, anti‐TIM‐3, and anti‐TIGIT, on T regulatory cells to elicit potent anti‐tumor immunities.

Radiotherapy has been used for the treatment of cancer for over a century. Throughout this period, the therapeutic benefit of radiotherapy has continuously progressed due to technical developments and increased insight in the biological mechanisms underlying the cellular responses to irradiation. In order to further improve radiotherapy efficacy, there is a mounting interest in combining radiotherapy with other forms of therapy such as anti-angiogenic therapy or immunotherapy. These strategies provide different opportunities and challenges, especially with regard to dose scheduling and timing. Addressing these issues requires insight in the interaction between the different treatment modalities. In the current review, we describe the basic principles of the effects of radiotherapy on tumor vascularization and tumor immunity and vice versa. We discuss the main strategies to combine these treatment modalities and the hurdles that have to be overcome in order to maximize therapeutic effectivity. Finally, we evaluate the outstanding questions and present future prospects of a therapeutic triad for cancer.

The role of inflammation in cardiovascular disease (CVD) is now widely accepted. Immune cells, including T cells, are influenced by inflammatory signals and contribute to the onset and progression of CVD. T cell activation is modulated by T cell co-stimulation and co-inhibition pathways. Immune checkpoint inhibitors (ICIs) targeting T cell inhibition pathways have revolutionized cancer treatment and improved survival in patients with cancer. However, ICIs might induce cardiovascular toxicity via T cell re-invigoration. With the rising use of ICIs for cancer treatment, a timely overview of the role of T cell co-stimulation and inhibition molecules in CVD is desirable. In this Review, the importance of these molecules in the pathogenesis of CVD is highlighted in preclinical studies on models of CVD such as vein graft disease, myocarditis, graft arterial disease, post-ischaemic neovascularization and atherosclerosis. This Review also discusses the therapeutic potential of targeting T cell co-stimulation and inhibition pathways to treat CVD, as well as the possible cardiovascular benefits and adverse events after treatment. Finally, the Review emphasizes that patients with cancer who are treated with ICIs should be monitored for CVD given the reported association between the use of ICIs and the risk of cardiovascular toxicity.This Review summarizes the preclinical data on the role of T cell co-stimulatory and co-inhibitory pathways in cardiovascular disease (CVD) and discusses the therapeutic potential of targeting co-stimulation and inhibition molecules to treat CVD, as well as the evidence of an association between the use of immune checkpoint inhibitors and cardiovascular toxicity.

Currently, a marked number of clinical trials on cancer treatment have revealed the success of immunomodulatory therapies based on immune checkpoint inhibitors that activate tumor-specific T cells. However, the therapeutic efficacy of cancer immunotherapies is only restricted to a small fraction of patients. A deeper understanding of key mechanisms generating an immunosuppressive tumor microenvironment (TME) remains a major challenge for more effective antitumor immunity. There is a growing evidence that the TME supports inappropriate metabolic reprogramming that dampens T cell function, and therefore impacts the antitumor immune response and tumor progression. Notably, the immunosuppressive TME is characterized by a lack of crucial carbon sources critical for T cell function and increased inhibitory signals. Here, we summarize the basics of intrinsic and extrinsic metabolic remodeling and metabolic checkpoints underlying the competition between cancer and infiltrating immune cells for nutrients and metabolites. Intriguingly, the upregulation of tumor programmed death-L1 and cytotoxic T lymphocyte-associated antigen 4 alters the metabolic programme of T cells and drives their exhaustion. In this context, targeting both tumor and T cell metabolism can beneficially enhance or temper immunity in an inhospitable microenvironment and markedly improve the success of immunotherapies.

In multiple tumor types, prediction of response to immune therapies relates to the presence, distribution and activation state of tumor infiltrating lymphocytes (TILs). Although such therapies are, to date, unsuccessful in gliomas, little is known on the immune contexture of TILs in these tumors. We assessed whether low and high-grade glioma (LGG and HGG, grade II and IV respectively) differ with respect to number, location and tumor reactivity of TILs; as well as expression of molecules involved in the trafficking and activation of T cells. Intra-tumoral CD8 T cells were quantified by flow cytometry (LGG: n = 12; HGG: n = 8) and immunofluorescence (LGG: n = 28; HGG: n = 28). Neoantigen load and expression of Cancer Germline Antigens (CGAs) were assessed using whole exome sequencing and RNA-seq. TIL-derived DNA was sequenced and the variable domain of the TCRβ chain was classified according to IMGT nomenclature. QPCR was used to determine expression of T cell-related genes. CD8 T cell numbers were significantly lower in LGG and, in contrast to HGG, mainly remained in close vicinity to blood vessels. This was accompanied by lower expression of chemo-attractants CXCL9 , CXCL10 and adhesion molecule ICAM1 . We did not observe a difference in the number of expressed neoantigens or CGAs, nor in diversity of TCR-Vβ gene usage. In summary, LGG have lower numbers of intra-tumoral CD8 T cells compared to HGG, potentially linked to decreased T cell trafficking. We have found no evidence for distinct tumor reactivity of T cells in either tumor type. The near absence of TILs in LGG suggest that, at present, checkpoint inhibitors are unlikely to have clinical efficacy in this tumor type.

Systemic sclerosis (SSc) is an autoimmune T-cell disease that is characterized by pathological fibrosis of the skin and internal organs. SSc is considered a prototype condition for studying the links between autoimmunity and fibrosis. Costimulatory pathways such as CD28/CTLA-4, ICOS-B7RP1, CD70-CD27, CD40-CD154, or OX40-OX40L play an essential role in the modulation of T-cell and inflammatory immune responses. A growing body of evidence suggests that T-cell costimulation signals might be implicated in the pathogenesis of SSc. CD28, CTLA-4, ICOS, and OX40L are overexpressed in patients with SSc, particularly in patients with cutaneous diffuse forms. In pre-clinical models of SSc, T-cell costimulation blockade with abatacept (CTLA-4-Ig) prevented and induced the regression of inflammation-driven dermal fibrosis, improved digestive involvement, prevented lung fibrosis, and attenuated pulmonary hypertension in complementary models of SSc. Likewise, potent anti-fibrotic effects were seen with the blockade of OX40L by reducing the infiltration of inflammatory cells into lesional tissues leading to decreased fibroblast activation. Concerning clinical effects, a preliminary observational study suggested some effectiveness of abatacept on inflammatory joint involvement, whereas clinical improvement of skin fibrosis was observed in a small placebo-controlled randomized trial. Currently there is one ongoing phase II clinical trial assessing the efficacy of abatacept in SSc (ASSET trial, NCT02161406). Overall, given the lack of available effective agents and the known toxic effects of immunosuppressive agents approved for use in SSc, costimulatory pathways offer the advantage of a targeted approach to costimulatory signals and potentially a better safety profile.

The immune checkpoint molecules are emerged in the evolution to protect the host from self-attacks by activated T cells. However, cancer cells, as a strategy to survive and expand, can hijack these molecules and mechanisms to suppress T cell-mediated immune responses. Therefore, an idea of blocking the checkpoint molecules to enhance the anti-tumor activities of the host immune system has been developed and applied to the cancer therapy after discovery of the inhibitory T cell co-receptor, cytotoxic T-lymphocyte associated protein 4 (CTLA-4), and further enhanced on the identification of PD-1 and its ligands. Since 2010, several checkpoint inhibitors have been approved by FDA and many more are in clinical trials. In the treatment of advanced cancers, these inhibitors significantly increased response rates and survival benefits. However, accompanied with the striking results, immune-related adverse events (irAEs) that broadly occurred in many organs were observed and reported, some of which were fatal. Herein, we first review the recent progressions in the research of the immune checkpoint molecules and the application of their blocking antibodies in cancer treatment, and then discuss the cardiac toxicity induced by the therapy and the strategy to monitor, manage this adverse event when it occurs.