All tumors harbor unique mutant peptides, some of which are able to elicit T-cell–mediated immune responses. These are known as neoantigens. Lung cancers bear a heavy mutational burden and hence many ...potential neoantigens. Neoantigens are increasingly recognized as key mediators of tumor-specific immune activation and have been identified as potential targets for personalized cancer therapies. In this review, we discuss the current data on neoantigens in lung cancer and provide an overview of the recent advances in neoantigen-based immunotherapy. Furthermore, we look ahead to highlight the major opportunities and challenges for the clinical application of neoantigen-based treatment strategies for thoracic and other malignancies.
Vancomycin is a prevalent cause of the severe hypersensitivity syndrome drug reaction with eosinophilia and systemic symptoms (DRESS), which leads to significant morbidity and mortality and commonly ...occurs in the setting of combination antibiotic therapy, affecting future treatment choices. Variations in HLA class I in particular have been associated with serious T cell–mediated adverse drug reactions, which has led to preventive screening strategies for some drugs.
We sought to determine whether variation in the HLA region is associated with vancomycin-induced DRESS.
Probable vancomycin-induced DRESS cases were matched 1:2 with tolerant control subjects based on sex, race, and age by using BioVU, Vanderbilt's deidentified electronic health record database. Associations between DRESS and carriage of HLA class I and II alleles were assessed by means of conditional logistic regression. An extended sample set from BioVU was used to conduct a time-to-event analysis of those exposed to vancomycin with and without the identified HLA risk allele.
Twenty-three subjects met the inclusion criteria for vancomycin-associated DRESS. Nineteen (82.6%) of 23 cases carried HLA-A*32:01 compared with 0 (0%) of 46 of the matched vancomycin-tolerant control subjects (P = 1 × 10−8) and 6.3% of the BioVU population (n = 54,249, P = 2 × 10−16). Time-to-event analysis of DRESS development during vancomycin treatment among the HLA-A*32:01–positive group indicated that 19.2% had DRESS and did so within 4 weeks.
HLA-A*32:01 is strongly associated with vancomycin-induced DRESS in a population of predominantly European ancestry. HLA-A*32:01 testing could improve antibiotic safety, help implicate vancomycin as the causal drug, and preserve future treatment options with coadministered antibiotics.
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Asbestos-induced preclinical mouse models of mesothelioma produce tumors that are very similar to those that develop in humans and thus represent an ideal platform to study this rare, universally ...fatal tumor type. Our team and a number of other research groups have established such models as a stepping stone to new treatments, including chemotherapy, immunotherapy and other approaches that have been/are being translated into clinical trials. In some cases this work has led to changes in mesothelioma treatment practice and over the last 30 years these models and studies have led to trials which have improved the response rate in mesothelioma from less than 10% to over 50%. Mouse models have had a vital role in that improvement and will continue to play a key role in the future success of mesothelioma immunotherapy. In this review we focus only on these original inbred mouse models, the large number of preclinical studies conducted using them and their contribution to current and future clinical therapy for mesothelioma.
The process of tumorigenesis leaves a series of indelible genetic changes in tumor cells, that when expressed, have the potential to be tumor-specific immune targets. Neoantigen vaccines that ...capitalize on this potential immunogenicity have shown efficacy in preclinical models and have now entered clinical trials. Here we discuss the status of personalized neoantigen vaccines and the current major challenges to this nascent field. In particular, we focus on the types of antigens that can be targeted by vaccination and on the role that preexisting immunosuppression, and in particular T-cell exhaustion, will play in the development of effective cancer vaccines.
Upon infection with an intracellular pathogen, cytotoxic CD8
T cells develop diverse differentiation states characterized by function, localization, longevity, and the capacity for self-renewal. The ...program of differentiation is determined, in part, by FOXO1, a transcription factor known to integrate extrinsic input in order to specify survival, DNA repair, self-renewal, and proliferation. At issue is whether the state of T cell differentiation is specified by initial conditions of activation or is actively maintained. To study the spectrum of T cell differentiation, we have analyzed an infection with mouse cytomegalovirus, a persistent-latent virus that elicits different cytotoxic T cell responses characterized as acute resolving or inflationary. Our results show that FOXO1 is continuously required for all the phenotypic characteristics of memory-effector T cells such that with acute inactivation of the gene encoding FOXO1, T cells revert to a short-lived effector phenotype, exhibit reduced viability, and manifest characteristics of anergy.
Cytomegaloviruses (CMVs) use myeloid cells to move within their hosts. Murine CMV (MCMV) colonizes the salivary glands for long-term shedding, and reaches them via CD11c
infected cells. A need to ...recruit patrolling monocytes for systemic spread has been proposed, based on poor salivary gland infection in fractalkine receptor (CX3CR1)-deficient mice. We found no significant CX3CR1 dependence of salivary gland infection. CCL2 and the viral m131/m129 chemokine homologue were also redundant for acute MCMV spread, arguing against a need for inflammation or infection to recruit additional monocytes to the entry site. M131/m129 promoted salivary gland infection, but only after the initial seeding of infected cells to this site. Our data support the idea that MCMV disseminates by infecting and mobilizing tissue-resident dendritic cells.
Adverse drug reactions (ADRs) are a significant health care burden. Immune-mediated adverse drug reactions (IM-ADRs) are responsible for one-fifth of ADRs but contribute a disproportionately high ...amount of that burden due to their severity. Variation in human leukocyte antigen (
HLA
) genes has emerged as a potential preprescription screening strategy for the prevention of previously unpredictable IM-ADRs. Immunopharmacogenomics combines the disciplines of immunogenomics and pharmacogenomics and focuses on the effects of immune-specific variation on drug disposition and IM-ADRs. In this review, we present the latest evidence for HLA associations with IM-ADRs, ongoing research into biological mechanisms of IM-ADRs, and the translation of clinical actionable biomarkers for IM-ADRs, with a focus on T cell-mediated ADRs.
Modern human activity fueled by economic development is profoundly altering our relationship with microorganisms. This altered interaction with microbes is believed to be the major driving force ...behind the increased rate of emerging infectious diseases from animals. The spate of recent infectious disease outbreaks, including Ebola virus disease and Middle East respiratory syndrome, emphasize the need for development of new innovative tools to manage these emerging diseases. Disseminating vaccines are one such novel approach to potentially interrupt animal to human (zoonotic) transmission of these pathogens.
Interleukin-22 (IL-22) is a member of the IL-10 family of cytokines. Hematopoietic cells express IL-22, and this cytokine signals through the heterodimeric IL-22 receptor expressed by ...non-hematopoietic cells. A growing body of evidence points toward a role for IL-22 in a diverse array of biological functions ranging from cellular proliferation, tissue protection and regeneration, and inflammation. In recent years, the role that IL-22 plays in antiviral immune responses has been examined in a number of infection models. Herein, we assess our current understanding of how IL-22 determines the outcome of viral infections and define common mechanisms that are evident from, sometimes paradoxical, findings derived from these studies. Finally, we discuss the potential therapeutic utility of IL-22 manipulation in the treatment and prevention of viral infections and associated pathologies.
Tissue-resident memory T (T
) cells provide first-line defense against invading pathogens encountered at barrier sites. In the lungs, T
cells protect against respiratory infections, but wane more ...quickly than T
cells in other tissues. This lack of a sustained T
population in the lung parenchyma explains, at least in part, why infections with some pathogens, such as influenza virus and respiratory syncytial virus (RSV), recur throughout life. Intranasal (IN) vaccination with a murine cytomegalovirus (MCMV) vector expressing the M protein of RSV (MCMV-M) has been shown to elicit robust populations of CD8
T
cells that accumulate over time and mediate early viral clearance. To extend this finding, we compared the inflationary CD8
T cell population elicited by MCMV-M vaccination with a conventional CD8
T cell population elicited by an MCMV vector expressing the M2 protein of RSV (MCMV-M2). Vaccination with MCMV-M2 induced a population of M2-specific CD8
T
cells that waned rapidly, akin to the M2-specific CD8
T
cell population elicited by infection with RSV. In contrast to the natural immunodominance profile, however, coadministration of MCMV-M and MCMV-M2 did not suppress the M-specific CD8
T cell response, suggesting that progressive expansion was driven by continuous antigen presentation, irrespective of the competitive or regulatory effects of M2-specific CD8
T cells. Moreover, effective viral clearance mediated by M-specific CD8
T
cells was not affected by the coinduction of M2-specific CD8
T cells. These data show that memory inflation is required for the maintenance of CD8
T
cells in the lungs after IN vaccination with MCMV.
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