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Extracellular vesicles have emerged as prominent regulators of the immune response during tumor progression. EVs contain a diverse repertoire of molecular cargo that plays a critical role in immunomodulation. Here, we identify the role of EVs as mediators of communication between cancer and immune cells. This expanded role of EVs may shed light on the mechanisms behind tumor progression and provide translational diagnostic and prognostic tools for immunologists. Extracellular vesicles (EVs) can exert potent immunomodulatory effects. Wirtz and colleagues review the types of EV and their influence on tumor responses.

The metabolically hostile tumour microenvironment imposes barriers to tumour-infiltrating immune cells and impedes durable clinical remission following immunotherapy. Metabolic communication between cancer cells and their neighbouring immune cells could determine the amplitude and type of immune responses, highlighting a potential involvement of metabolic crosstalk in immune surveillance and escape. In this Review, we explore tumour–immune metabolic crosstalk and discuss potential nutrient-limiting strategies that favour anti-tumour immune responses. Kao et al. discuss the metabolic crosstalk between cancer cells and immune cells and how this impacts immune surveillance and anti-tumour immune responses.

The microenvironment in cancerous tissues is immunosuppressive and pro-tumorigenic, whereas the microenvironment of tissues affected by chronic inflammatory disease is pro-inflammatory and anti-resolution. Despite these opposing immunological states, the metabolic states in the tissue microenvironments of cancer and inflammatory diseases are similar: both are hypoxic, show elevated levels of lactate and other metabolic by-products and have low levels of nutrients. In this Review, we describe how the bioavailability of lactate differs in the microenvironments of tumours and inflammatory diseases compared with normal tissues, thus contributing to the establishment of specific immunological states in disease. A clear understanding of the metabolic signature of tumours and inflammatory diseases will enable therapeutic intervention aimed at resetting the bioavailability of metabolites and correcting the dysregulated immunological state, triggering beneficial cytotoxic, inflammatory responses in tumours and immunosuppressive responses in chronic inflammation.Lactate accumulates in cancerous and chronically inflamed tissues, where it has diverse and often opposing effects. Here, the authors review the activities of this metabolite in these distinct circumstances, identifying opportunities for therapeutic modulation of the metabolic signature in tumours and inflammatory diseases.

The unceasing circulation of SARS-CoV-2 leads to the continuous emergence of novel viral sublineages. Here, we isolate and characterize XBB.1, XBB.1.5, XBB.1.9.1, XBB.1.16.1, EG.5.1.1, EG.5.1.3, XBF, BA.2.86.1 and JN.1 variants, representing >80% of circulating variants in January 2024. The XBB subvariants carry few but recurrent mutations in the spike, whereas BA.2.86.1 and JN.1 harbor >30 additional changes. These variants replicate in IGROV-1 but no longer in Vero E6 and are not markedly fusogenic. They potently infect nasal epithelial cells, with EG.5.1.3 exhibiting the highest fitness. Antivirals remain active. Neutralizing antibody (NAb) responses from vaccinees and BA.1/BA.2-infected individuals are markedly lower compared to BA.1, without major differences between variants. An XBB breakthrough infection enhances NAb responses against both XBB and BA.2.86 variants. JN.1 displays lower affinity to ACE2 and higher immune evasion properties compared to BA.2.86.1. Thus, while distinct, the evolutionary trajectory of these variants combines increased fitness and antibody evasion. SARS-CoV-2 evolved into several sublineages harboring different mutations in spike. Here, the authors isolate and characterize nine SARS-CoV-2 variants and show that EG.5.1.3 has highest fitness in nasal epithelial cells, while JN.1 shows lower affinity to ACE2 and higher immune evasion compared to BA.2.86.1.

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) B.1.1.7 and B.1.351 variants were first identified in the United Kingdom and South Africa, respectively, and have since spread to many countries. These variants harboring diverse mutations in the gene encoding the spike protein raise important concerns about their immune evasion potential. Here, we isolated infectious B.1.1.7 and B.1.351 strains from acutely infected individuals. We examined sensitivity of the two variants to SARS-CoV-2 antibodies present in sera and nasal swabs from individuals infected with previously circulating strains or who were recently vaccinated, in comparison with a D614G reference virus. We utilized a new rapid neutralization assay, based on reporter cells that become positive for GFP after overnight infection. Sera from 58 convalescent individuals collected up to 9 months after symptoms, similarly neutralized B.1.1.7 and D614G. In contrast, after 9 months, convalescent sera had a mean sixfold reduction in neutralizing titers, and 40% of the samples lacked any activity against B.1.351. Sera from 19 individuals vaccinated twice with Pfizer Cominarty, longitudinally tested up to 6 weeks after vaccination, were similarly potent against B.1.1.7 but less efficacious against B.1.351, when compared to D614G. Neutralizing titers increased after the second vaccine dose, but remained 14-fold lower against B.1.351. In contrast, sera from convalescent or vaccinated individuals similarly bound the three spike proteins in a flow cytometry-based serological assay. Neutralizing antibodies were rarely detected in nasal swabs from vaccinees. Thus, faster-spreading SARS-CoV-2 variants acquired a partial resistance to neutralizing antibodies generated by natural infection or vaccination, which was most frequently detected in individuals with low antibody levels. Our results indicate that B1.351, but not B.1.1.7, may increase the risk of infection in immunized individuals. Sera from convalescent individuals with coronavirus disease 2019 and from individuals vaccinated with BNT162b2 have reduced ability to neutralize SARS-CoV-2 variants B1.1.7 and B.1.351, but antibody potency against the variants increases after two vaccine doses.

Continuous evolution of Omicron has led to a rapid and simultaneous emergence of numerous variants that display growth advantages over BA.5 (ref. 1 ). Despite their divergent evolutionary courses, mutations on their receptor-binding domain (RBD) converge on several hotspots. The driving force and destination of such sudden convergent evolution and its effect on humoral immunity remain unclear. Here we demonstrate that these convergent mutations can cause evasion of neutralizing antibody drugs and convalescent plasma, including those from BA.5 breakthrough infection, while maintaining sufficient ACE2-binding capability. BQ.1.1.10 (BQ.1.1 + Y144del), BA.4.6.3, XBB and CH.1.1 are the most antibody-evasive strains tested. To delineate the origin of the convergent evolution, we determined the escape mutation profiles and neutralization activity of monoclonal antibodies isolated from individuals who had BA.2 and BA.5 breakthrough infections 2 , 3 . Owing to humoral immune imprinting, BA.2 and especially BA.5 breakthrough infection reduced the diversity of the neutralizing antibody binding sites and increased proportions of non-neutralizing antibody clones, which, in turn, focused humoral immune pressure and promoted convergent evolution in the RBD. Moreover, we show that the convergent RBD mutations could be accurately inferred by deep mutational scanning profiles 4 , 5 , and the evolution trends of BA.2.75 and BA.5 subvariants could be well foreseen through constructed convergent pseudovirus mutants. These results suggest that current herd immunity and BA.5 vaccine boosters may not efficiently prevent the infection of Omicron convergent variants. Convergent mutations in hotspots of the SARS-CoV-2 Omicron receptor-binding domain can cause immune evasion and maintain sufficient ACE2-binding capability.

Key Points Periodontitis is a dysbiotic oral disease that increases the patients' risk of developing systemic inflammatory disorders. The dysbiosis of the periodontal microbiota is characterized by an imbalance in the relative abundance or influence of microbial species with distinct roles that converge to shape a pathogenic microbial community. Within the community, periodontal bacteria use sophisticated strategies to evade immune-mediated killing while promoting a nutritionally favourable inflammatory response. The host response is initially subverted by keystone pathogens with the aid of accessory pathogens and is subsequently overactivated by the emerging pathobionts, which leads to destructive inflammation. Periodontal bacteria (including Porphyromonas gingivalis ) have been detected in circulating leukocytes and in aortic tissues, where clinical and mechanistic animal-model studies indicate that they act as pro-atherogenic stimuli. P. gingivalis expresses a unique citrullinating enzyme that is involved in the generation of autoantibodies that contribute to the pathogenesis of rheumatoid arthritis. Bacteria that originate from the periodontal tissue (such as Fusobacterium nucleatum ) have been detected in the placenta, where they can cause adverse pregnancy outcomes, as suggested by clinical and mechanistic evidence. The periodontal biofilm also acts as a reservoir for respiratory infections and for exacerbations of chronic obstructive pulmonary disease in synergy with local opportunistic pathogens. Understanding how oral pathogens subvert the host response at the molecular level will not only provide insights into the pathogenesis of periodontitis and associated systemic conditions, but could also reveal new therapeutic targets. Periodontitis has been linked to systemic inflammatory conditions such as rheumatoid arthritis. In this Review, the author summarizes these links and discusses the mechanisms of microbial immune subversion that tip the balance from homeostasis to disease at oral or distant sites. Periodontitis is a dysbiotic inflammatory disease with an adverse impact on systemic health. Recent studies have provided insights into the emergence and persistence of dysbiotic oral microbial communities that can mediate inflammatory pathology at local as well as distant sites. This Review discusses the mechanisms of microbial immune subversion that tip the balance from homeostasis to disease in oral or extra-oral sites.

Key Points Somatic mutations can cause tumours to express mutant proteins that are tumour specific and not expressed on normal cells (neoantigens). In the subset of human tumours with a viral aetiology, the proteins encoded by viral genes are another type of neoantigen. Neoantigens are an attractive immune target because their selective expression on tumours may minimize immune tolerance as well as the risk of autoimmunity. Therefore, neoantigen-specific therapies may be more effective and less toxic than therapies targeting tumour-associated antigens. Neoantigens serve a crucial role in the naturally occurring antitumour T cell response, and are also the most important tumour antigens in certain cancers for which immune checkpoint inhibitors have shown clinical efficacy. As neoantigens are unique and not shared between different patients, neoantigen-targeted therapy will probably need to be on an individual basis. A personalized approach to targeting neoantigens has only recently been possible as a result of major advances in genomics and bioinformatics, including massively parallel sequencing and epitope prediction algorithms. Two therapeutic platforms that could be used to target neoantigens are adoptive cell therapy (ACT) using neoantigen-specific T cell products, and personalized vaccines encoding predicted neoantigens. Neoantigen-specific therapies will probably need to be combined with other therapies such as immune checkpoint inhibitors to overcome immunosuppressive mechanisms in the tumour microenvironment that inhibit neoantigen-specific immune responses. In this Review, Yarchoan et al . discuss the potential of targeting tumour-specific antigens (neoantigens) to increase antitumour immunity and present a framework for personalized cancer immunotherapy based on the identification and specific targeting of individual tumour neoantigens. The past decade of cancer research has been marked by a growing appreciation of the role of immunity in cancer. Mutations in the tumour genome can cause tumours to express mutant proteins that are tumour specific and not expressed on normal cells (neoantigens). These neoantigens are an attractive immune target because their selective expression on tumours may minimize immune tolerance as well as the risk of autoimmunity. In this Review we discuss the emerging evidence that neoantigens are recognized by the immune system and can be targeted to increase antitumour immunity. We also provide a framework for personalized cancer immunotherapy through the identification and selective targeting of individual tumour neoantigens, and present the potential benefits and obstacles to this approach of targeted immunotherapy.

Glioblastoma (GBM) is the deadliest form of brain cancer, with a median survival of less than 2 years despite surgical resection, radiation, and chemotherapy. GBM’s rapid progression, resistance to therapy, and inexorable recurrence have been attributed to several factors, including its rapid growth rate, its molecular heterogeneity, its propensity to infiltrate vital brain structures, the regenerative capacity of treatment-resistant cancer stem cells, and challenges in achieving high concentrations of chemotherapeutic agents in the central nervous system. Escape from immunosurveillance is increasingly recognized as a landmark event in cancer biology. Translation of this framework to clinical oncology has positioned immunotherapy as a pillar of cancer treatment. Amid the bourgeoning successes of cancer immunotherapy, GBM has emerged as a model of resistance to immunotherapy. Here we review the mechanisms of immunotherapy resistance in GBM and discuss how insights into GBM–immune system interactions might inform the next generation of immunotherapeutics for GBM and other resistant pathologies. High-grade glioblastoma demonstrates exceedingly poor patient survival rates. In their Review, Lim and colleagues describe the immunological mechanisms involved in the control of glioblastoma and the outlook for immunotherapy.

Key Points Therapeutic vaccines for the induction of tumour-specific T cell responses show high immunogenicity and clinical efficacy over different formulation platforms in pre-cancers but not in established cancers. Cancer vaccines fail to treat established disease owing to a lack of appropriate co-treatment for the immune evasion mechanisms that are operational in the target group. Recognition of escaped tumours with defective major histocompatibility complex (MHC) class I processing and presentation can, in most cases, be restored or induced by activation of CD8 + T cells specific for T cell epitopes associated with impaired peptide processing (TEIPP) antigens. The potency of peptide-based vaccines to stimulate type 1 T helper (T H 1) cells and CD8 + T cells will be improved by coupling them with pattern recognition receptor (PRR) agonists and by the formation of supramolecular peptide conjugates. The combination of vaccines with therapies that target immune-suppressive myeloid cells, prevent immune checkpoint activation and stimulate local immune cell infiltration will maximize clinical benefit. Future research will focus on methods to quickly assess the most important immunological hurdles present in a patient's tumour so that the best cancer vaccine combination therapy can be given. This Review summarizes immune evasion mechanisms that limit the therapeutic efficacy of cancer vaccines. The authors discuss how improving vaccine design and using vaccines in combination with other anticancer therapies can boost treatment efficacy in patients with established cancers. Therapeutic vaccines preferentially stimulate T cells against tumour-specific epitopes that are created by DNA mutations or oncogenic viruses. In the setting of premalignant disease, carcinoma in situ or minimal residual disease, therapeutic vaccination can be clinically successful as monotherapy; however, in established cancers, therapeutic vaccines will require co-treatments to overcome immune evasion and to become fully effective. In this Review, we discuss the progress that has been made in overcoming immune evasion controlled by tumour cell-intrinsic factors and the tumour microenvironment. We summarize how therapeutic benefit can be maximized in patients with established cancers by improving vaccine design and by using vaccines to increase the effects of standard chemotherapies, to establish and/or maintain tumour-specific T cells that are re-energized by checkpoint blockade and other therapies, and to sustain the antitumour response of adoptively transferred T cells.