A Cancer Nanovaccine for Co-Delivery of Peptide Neoantigens and Optimized Combinations of STING and TLR4 Agonists.

Immune checkpoint blockade (ICB) has revolutionized cancer treatment and led to complete and durable responses, but only for a minority of patients. Resistance to ICB can largely be attributed to insufficient number and/or function of antitumor CD8 T cells in the tumor microenvironment. Neoantigen targeted cancer vaccines can activate and expand the antitumor T cell repertoire, but historically, clinical responses have been poor because immunity against peptide antigens is typically weak, resulting in insufficient activation of CD8 cytotoxic T cells.

-the struggles and battles of innate-like effector T lymphocytes with microbes.

The large majority of lymphocytes belong to the adaptive immune system, which are made up of B2 B cells and the αβ T cells; these are the effectors in an adaptive immune response. A multitudinous group of lymphoid lineage cells does not fit the conventional lymphocyte paradigm; it is the unconventional lymphocytes. Unconventional lymphocytes-here called innate/innate-like lymphocytes, include those that express rearranged antigen receptor genes and those that do not.

The ion channel CALHM6 controls bacterial infection-induced cellular cross-talk at the immunological synapse.

Membrane ion channels of the calcium homeostasis modulator (CALHM) family promote cell-cell crosstalk at neuronal synapses via ATP release, where ATP acts as a neurotransmitter. CALHM6, the only CALHM highly expressed in immune cells, has been linked to the induction of natural killer (NK) cell anti-tumour activity. However, its mechanism of action and broader functions in the immune system remain unclear.

Thymic epithelial cells require lipid kinase Vps34 for CD4 but not CD8 T cell selection.

The generation of a functional, self-tolerant T cell receptor (TCR) repertoire depends on interactions between developing thymocytes and antigen-presenting thymic epithelial cells (TECs). Cortical TECs (cTECs) rely on unique antigen-processing machinery to generate self-peptides specialized for T cell positive selection. In our current study, we focus on the lipid kinase Vps34, which has been implicated in autophagy and endocytic vesicle trafficking.

A single-cell analysis of thymopoiesis and thymic iNKT cell development in pigs.

Many aspects of the porcine immune system remain poorly characterized, which poses a barrier to improving swine health and utilizing pigs as preclinical models. Here, we employ single-cell RNA sequencing (scRNA-seq) to create a cell atlas of the early-adolescent pig thymus. Our data show conserved features as well as species-specific differences in cell states and cell types compared with human thymocytes.

A nanovaccine for enhancing cellular immunity via cytosolic co-delivery of antigen and polyIC RNA.

Traditional approaches to cancer vaccines elicit weak CD8 T cell responses and have largely failed to meet clinical expectations. This is in part due to inefficient antigen cross-presentation, inappropriate selection of adjuvant and its formulation, poor vaccine pharmacokinetics, and/or suboptimal coordination of antigen and adjuvant delivery. Here, we describe a nanoparticle vaccine platform for facile co-loading and dual-delivery of antigens and nucleic acid adjuvants that elicits robust antigen-specific cellular immune responses.

Nano-Particulate Platforms for Vaccine Delivery to Enhance Antigen-Specific CD8 T-Cell Response.

Vaccines remain the most effective way to protect populations against deathly infectious diseases. Several disadvantages associated with the traditional vaccines that use whole pathogens have led to the development of alternative strategies including the use of recombinant subunit vaccines. Subunit vaccines are, in general, safer than whole pathogens but tend to be less immunogenic due to the lack of molecular cues that are typically found on whole pathogens.

Novel HLA-B7-restricted human metapneumovirus epitopes enhance viral clearance in mice and are recognized by human CD8 T cells.

Human metapneumovirus (HMPV) is a leading cause of acute lower respiratory tract illness in children and adults. Repeated infections are common and can be severe in young, elderly, and immunocompromised persons due to short-lived protective humoral immunity. In turn, few protective T cell epitopes have been identified in humans.

Know thy immune self and non-self: Proteomics informs on the expanse of self and non-self, and how and where they arise.

T cells play an important role in the adaptive immune response to a variety of infections and cancers. Initiation of a T cell mediated immune response requires antigen recognition in a process termed MHC (major histocompatibility complex) restri ction. A T cell antigen is a composite structure made up of a peptide fragment bound within the antigen-binding groove of an MHC-encoded class I or class II molecule.

Natural Killer T Lymphocytes Integrate Innate Sensory Information and Relay Context to Effector Immune Responses.

It is now appreciated that a group of lymphoid lineage cells, collectively called innate-like effector lymphocytes, have evolved to integrate information relayed by the innate sensory immune system about the state of the local tissue environment and to pass on this context to downstream effector innate and adaptive immune responses. Thereby, innate functions engrained into such innate-like lymphoid lineage cells during development can control the quality and magnitude of an immune response to a tissue-altering pathogen and facilitate the formation of memory engrams within the immune system. These goals are accomplished by the innate lymphoid cells that lack antigen-specific receptors, γδ T cell receptor (TCR)-expressing T cells, and several αβ TCR-expressing T cell subsets-such as natural killer T cells, mucosal-associated invariant T cells, et cetera.

Heterotypic immunity against vaccinia virus in an HLA-B*07:02 transgenic mousepox infection model.

Vaccination with vaccinia virus (VACV) elicits heterotypic immunity to smallpox, monkeypox, and mousepox, the mechanistic basis for which is poorly understood. It is generally assumed that heterotypic immunity arises from the presentation of a wide array of VACV-derived, CD8 T cell epitopes that share homology with other poxviruses. Herein this assumption was tested using a large panel of VACV-derived peptides presented by HLA-B*07:02 (B7.

Co-delivery of Peptide Neoantigens and Stimulator of Interferon Genes Agonists Enhances Response to Cancer Vaccines.

Cancer vaccines targeting patient-specific neoantigens have emerged as a promising strategy for improving responses to immune checkpoint blockade. However, neoantigenic peptides are poorly immunogenic and inept at stimulating CD8 T cell responses, motivating a need for new vaccine technologies that enhance their immunogenicity. The stimulator of interferon genes (STING) pathway is an endogenous mechanism by which the innate immune system generates an immunological context for priming and mobilizing neoantigen-specific T cells.

Nur77 controls tolerance induction, terminal differentiation, and effector functions in semi-invariant natural killer T cells.

Semi-invariant natural killer T (iNKT) cells are self-reactive lymphocytes, yet how this lineage attains self-tolerance remains unknown. iNKT cells constitutively express high levels of -encoded Nur77, a transcription factor that integrates signal strength downstream of the T cell receptor (TCR) within activated thymocytes and peripheral T cells. The function of Nur77 in iNKT cells is unknown.

Survivre et vivre: When iNKT cells met a Hippo.

Invariant natural killer T (iNKT) cells are innate-like lymphocytes with unique signaling requirements for their development and differentiation. In this issue of JEM, Raynor et al. (https://doi.

NKT Cells Join the Two Step for Inflammasome-Independent IL-1β Release.

The cytokine interleukin-1β (IL-1β) is critical for antimicrobial defenses; the inflammasome pathway typically controls IL-1β release, but pathogens often evade this pathway. In this issue, Donado et al. (2020) describe an alternative, two-cell model, to instruct inflammasome-independent IL-1β release.

What one lipid giveth, another taketh away.

Acid sphingomyelinase deficiency, which prevents degradation of sphingomyelin (SM), causes lysosomal SM overload both in mice and in patients with Niemann–Pick disease A or B. Altered cellular SM homeostasis disrupts the development and function of natural killer T cells by obstructing the presentation of lipid agonists by CD1d molecules.

Mucosal Immunization with a pH-Responsive Nanoparticle Vaccine Induces Protective CD8 Lung-Resident Memory T Cells.

Tissue-resident memory T cells (T) patrol nonlymphoid organs and provide superior protection against pathogens that commonly infect mucosal and barrier tissues, such as the lungs, intestine, liver, and skin. Thus, there is a need for vaccine technologies that can induce a robust, protective T response in these tissues. Nanoparticle (NP) vaccines offer important advantages over conventional vaccines; however, there has been minimal investigation into the design of NP-based vaccines for eliciting T responses.

AS03-Adjuvanted H5N1 Avian Influenza Vaccine Modulates Early Innate Immune Signatures in Human Peripheral Blood Mononuclear Cells.

Background: Adjuvant System 03 (AS03) markedly enhances responses to influenza A/H5N1 vaccines, but the mechanisms of this enhancement are incompletely understood.

Methods: Using ribonucleic acid sequencing on peripheral blood mononuclear cells (PBMCs) from AS03-adjuvanted and unadjuvanted inactivated H5N1 vaccine recipients, we identified differentially expressed genes, enriched pathways, and genes that correlated with serologic responses. We compared bulk PBMC findings with our previously published assessments of flow-sorted immune cell types.

Identifying and Tracking Low-Frequency Virus-Specific TCR Clonotypes Using High-Throughput Sequencing.

Tracking antigen-specific T cell responses over time within individuals is difficult because of lack of knowledge of antigen-specific TCR sequences, limitations in sample size, and assay sensitivities. We hypothesized that analyses of high-throughput sequencing of TCR clonotypes could provide functional readouts of individuals' immunological histories. Using high-throughput TCR sequencing, we develop a database of TCRβ sequences from large cohorts of mice before (naive) and after smallpox vaccination.

Loss of CXCR4 in Myeloid Cells Enhances Antitumor Immunity and Reduces Melanoma Growth through NK Cell and FASL Mechanisms.

The chemokine receptor, CXCR4, is involved in cancer growth, invasion, and metastasis. Several promising CXCR4 antagonists have been shown to halt tumor metastasis in preclinical studies, and clinical trials evaluating the effectiveness of these agents in patients with cancer are ongoing. However, the impact of targeting CXCR4 specifically on immune cells is not clear.

Poly(propylacrylic acid)-peptide nanoplexes as a platform for enhancing the immunogenicity of neoantigen cancer vaccines.

Cancer vaccines targeting patient-specific tumor neoantigens have recently emerged as a promising component of the rapidly expanding immunotherapeutic armamentarium. However, neoantigenic peptides typically elicit weak CD8 T cell responses, and so there is a need for universally applicable vaccine delivery strategies to enhance the immunogenicity of these peptides. Ideally, such vaccines could also be rapidly fabricated using chemically synthesized peptide antigens customized to an individual patient.

CD4 Regulatory T Cells Exert Differential Functions during Early and Late Stages of the Immune Response to Respiratory Viruses.

Acute respiratory virus infection (ARI) induces CD8 T cells with diminished cytokine production and functional impairment. The role of cellular mediators of immune impairment, specifically CD4 regulatory T cells (Tregs), is incompletely understood in ARI. Tregs are known suppressors of effector T cell function, but whether they are detrimental or beneficial in ARI remains controversial.

Natural Killer T Cells: An Ecological Evolutionary Developmental Biology Perspective.

Type I natural killer T (NKT) cells are innate-like T lymphocytes that recognize glycolipid antigens presented by the MHC class I-like protein CD1d. Agonistic activation of NKT cells leads to rapid pro-inflammatory and immune modulatory cytokine and chemokine responses. This property of NKT cells, in conjunction with their interactions with antigen-presenting cells, controls downstream innate and adaptive immune responses against cancers and infectious diseases, as well as in several inflammatory disorders.