A Novel Trained Immunity Adjuvant Derived From Commensal Bacteria Potentiates Liposome-Hydrogel Cancer Vaccine Against Breast Tumors.

Radiation-based immunogenic vaccine combined with a macrophage “checkpoint inhibitor” for boosting innate and adaptive immunity against metastatic colon cancers

How are airborne allergens remembered by the immune system?

Cancer vaccines hold great potential for clinical cancer treatment by eliciting T cell-mediated immunity. However, the limited numbers of antigen-presenting cells (APCs) at the injection sites, the insufficient tumor antigen phagocytosis by APCs, and the presence of a strong tumor immunosuppressive microenvironment severely compromise the efficacy of cancer vaccines. Trained innate immunity may promote tumor antigen-specific adaptive immunity. Here, a personalized cancer vaccine is developed by engineering the inactivated probiotic Escherichia coli Nissle 1917 to load tumor antigens and β-glucan, a trained immunity inducer. After subcutaneous injection, the cancer vaccine delivering model antigen OVA (BG/OVA@EcN) is highly accumulated and phagocytosed by macrophages at the injection sites to induce trained immunity. The trained macrophages may recruit dendritic cells (DCs) to facilitate BG/OVA@EcN phagocytosis and the subsequent DC maturation and T cell activation. In addition, BG/OVA@EcN remarkably enhances the circulating trained monocytes/macrophages, promoting differentiation into M1-like macrophages in tumor tissues. BG/OVA@EcN generates strong prophylactic and therapeutic efficacy to inhibit tumor growth by inducing potent adaptive antitumor immunity and long-term immune memory. Importantly, the cancer vaccine delivering autologous tumor antigens efficiently prevents postoperative tumor recurrence. This platform offers a facile translatable strategy to efficiently integrate trained immunity and adaptive immunity for personalized cancer immunotherapy.

The innate immunity is frequently accepted as a first line of relatively primitive defense interfering with the pathogen invasion until the mechanisms of 'privileged' adaptive immunity with the production of antibodies and activation of cytotoxic lymphocytes 'steal the show'. Recent advancements on the molecular and cellular levels have shaken the traditional view of adaptive and innate immunity. The innate immune memory or 'trained immunity' based on metabolic changes and epigenetic reprogramming is a complementary process insuring adaptation of host defense to previous infections.Innate immune cells are able to recognize large number of pathogen- or danger- associated molecular patterns (PAMPs and DAMPs) to behave in a highly specific manner and regulate adaptive immune responses. Innate lymphoid cells (ILC1, ILC2, ILC3) and NK cells express transcription factors and cytokines related to subsets of T helper cells (Th1, Th2, Th17). On the other hand, T and B lymphocytes exhibit functional properties traditionally attributed to innate immunity such as phagocytosis or production of tissue remodeling growth factors. They are also able to benefit from the information provided by pattern recognition receptors (PRRs), e.g. γδT lymphocytes use T-cell receptor (TCR) in a manner close to PRR recognition. Innate B cells represent another example of limited combinational diversity usage participating in various innate responses. In the view of current knowledge, the traditional black and white classification of immune mechanisms as either innate or an adaptive needs to be adjusted and many shades of gray need to be included.

Recent research has increasingly highlighted the adaptive characteristics of the innate immune system, revealing its capacity for a heterologous memory of previous infections. Allergen-specific immunotherapy (AIT) has demonstrated that innate immune cells, such as monocytes, macrophages, and natural killer (NK) cells, can provide protection against specific diseases even in the absence of lymphocyte support. The mechanisms underlying innate host defense and the immunological memory of adaptive immunity differ significantly in terms of cellular populations and molecular pathways. Prototypical innate immune cells, including NK cells and monocytes/macrophages, contribute to the sustained heightened state of innate immunity known as "trained immunity," which enhances resistance to secondary infections. Trained immunity is typically initiated through the engagement of pattern recognition receptors (PRRs) by microbial structures, suggesting that vaccines designed to induce trained immunity should incorporate appropriate PRR ligands. This approach not only offers protection against reinfection in a manner independent of T and B cells but also promotes nonspecific epigenetic reprogramming that enhances immune responses. For instance, Bacillus Calmette-Guérin (BCG) vaccination has been linked to long-lasting immune modifications associated with a non-specific immune response to various infections, characterized by heterologous T helper 1 (Th1) and Th17 responses. Emerging evidence indicates that heat-killed Mycobacterium manresensis can induce trained immunity in vitro, although its effectiveness in vivo remains to be fully established. This highlights the potential of novel strategies in vaccine development, particularly through the lens of trained immunity. The concept of trained immunity-based vaccines (TIbV) presents a paradigm shift in immunization strategies, as these vaccines can elicit broad-spectrum protection against a variety of pathogens. By leveraging the principles of trained immunity, TIbV can enhance both innate and adaptive immune responses, potentially improving the efficacy of conventional vaccines and offering new avenues for immunotherapy.The integration of trained innate immunity into vaccine development holds significant promise for enhancing immune protection against infectious diseases. By harnessing the principles of trained immunity, these innovative vaccines can enhance innate immune responses, potentially improving protection against a wide range of infectious diseases and contributing to better public health outcomes.

Current treatment options for ovarian cancer are limited to surgery to remove tumor tissues and chemotherapy. Although such treatments could provide a short period of remission, most patients still experience recurrent metastatic diseases. Here we present a nanotechnology-based personalized cancer vaccine that can be administrated to patients during the remission stage to prevent recurrent diseases. Autologous tumor cell lysates (TCL) are intriguing, personalized antigens that could be extracted from surgically recovered tumor tissues from patients containing all neoantigens. As proof of concept, we use TCL isolated from a murine ovarian cancer cell line. TCL are first encapsulated in liposomes (TCL-Lip), which are then attached to cowpea mosaic virus (CPMV), a plant virus as a potent adjuvant. Using the ID8-Defb29/Vegf-a-Luc tumor model in female mice, the TCL-Lip-CPMV conjugate vaccine protects mice from tumor challenge by improving antigen processing and presentation, priming an adaptive anti-tumor immunity. Using ovalbumin (OVA) as a model antigen, OVA-Lip-CPMV vaccination protects mice from lung metastasis post-surgical removal of the primary B16F10-OVA dermal tumors. This research establishes a platform by combining two nanoparticle technologies into a single formulation for the simultaneous delivery of antigens and adjuvants, advancing the development of cancer vaccines and immunotherapies.

Hepatocellular carcinoma (HCC) is a leading cause of cancer death globally, with the majority of cases detected at advanced stages when curative options are limited. Current systemic therapies, including immune checkpoint inhibitors, demonstrate limited efficacy with durable responses in only 15-20% of patients. This poor response is largely attributed to HCC's immunosuppressive microenvironment, which blunts effective T-cell responses. By illustrating that innate immune cells can acquire memory-like characteristics through a process known as trained immunity, recent evidence has challenged the conventional belief that innate immunity is devoid of memory. This review investigates the potential of trained immunity, which is defined by the long-term functional reprogramming of innate immune cells through epigenetic, transcriptomic, and metabolic changes, to provide new therapeutic opportunities for HCC. We discuss mechanisms by which trained immunity can transform the HCC microenvironment, including enhanced inflammatory cytokine production, repolarization of tumor-associated macrophages toward anti-tumor phenotypes, increased immune cell infiltration, and improved bridging to adaptive immunity. We further evaluate emerging therapeutic strategies leveraging trained immunity principles, including BCG vaccination, β-glucan administration, cytokine-trained NK cell therapy, and innovative combination approaches. Finally, we address potential resistance mechanisms and future directions for clinical application. By integrating trained immunity into conventional immunotherapeutic regimens, we may significantly improve outcomes for HCC patients, potentially transforming advanced disease into a more manageable condition.

Innate immune cells are critical in antitumor immune surveillance and the development of antitumor adaptive cellular immunity. Trained innate immune cells demonstrate immune memory-like characteristics, producing more vigorous immune responses to secondary homologous or heterologous stimuli. This study aimed to investigate whether inducing trained immunity is beneficial when using a tumor vaccine to promote antitumor adaptive immune responses. A biphasic delivery system was developed with the trained immunity inducer Muramyl Dipeptide (MDP) and specific tumor antigen human papillomavirus (HPV) E7 peptide encapsulated by poly(lactide-co-glycolide)-acid(PLGA) nanoparticles (NPs), and the NPs along with another trained immunity agonist, β-glucan, were further embedded in a sodium alginate hydrogel. The nanovaccine formulation demonstrated a depot effect for E7 at the injection site and targeted delivery to the lymph nodes and dendritic cells (DCs). The antigen uptake and maturation of DCs were significantly promoted. A trained immunity phenotype, characterized by increased production of IL-1β, IL-6, and TNF-α, was induced in vitro and in vivo in response to secondary homologous or heterologous stimulation. Furthermore, prior innate immune training enhanced the antigen-specific INF-γ-expressing immune cell response elicited by subsequent stimulation with the nanovaccine. Immunization with the nanovaccine completely inhibited the growth of TC-1 tumors and even abolished established tumors in mice. Mechanistically, the inclusion of β-glucan and MDP significantly enhanced the responses of tumor-specific effector adaptive immune cells. The results strongly suggest that the controlled release and targeted delivery of an antigen and trained immunity inducers with an NP/hydrogel biphasic system can elicit robust adaptive immunity, which provides a promising tumor vaccination strategy.Graphical

New immune therapy targets tumor-associated environment: from bone marrow to tumor site

Rheumatic diseases include a variety of autoimmune and autoinflammatory conditions that are characterised by musculoskeletal involvement and systemic disease. Both innate and adaptive immunity can contribute to the complex inflammatory processes that take part in the pathogenesis of these debilitating disorders. Over the past decade, studies have led to a paradigm-shift around the concept of immune memory, generating the knowledge that cells of the innate immune system can develop a de facto memory mediated by epigenetic reprograming and metabolic changes (trained immunity). Here we provide an overview of current data that describe features of trained immunity in rheumatic diseases. We link evidence on inflammatory mediators and cytokine production, immunometabolism and epigenetic regulation of immunological programs, and outline the fact that trained immunity could play mechanistic roles in rheumatic diseases such as gout, rheumatoid arthritis, systemic lupus erythematosus or systemic sclerosis. This review describes recent findings in several important rheumatic disorders and emphasizes changes in the functional program of innate immune cells that are reminiscent of a trained immune phenotype. Further assessment of trained immunity in rheumatic disease can provide targetable mechanisms that could potentially alter the disease symptomatology and evolution.

Trained innate immunity and resistance to Mycobacterium tuberculosis infection

ABSTRACTTrained immunity as a critical regulator of host defense and disease pathogenesis bridges the gap between innate and adaptive immunity. For decades, the classic dichotomy of innate immunity and adaptive immunity has shaped our knowledge of immune function. Innate immunity has traditionally been regarded as a rapid, nonspecific first line of defense without memory capacity, while adaptive immunity is characterized by slower, antigen‐specific responses and long‐term immune memory. However, emerging evidence that innate immunity exhibits memory‐like properties challenges the paradigm. Basically, innate immune cells with nonspecific memory retain functional imprints of prior encounters with diverse stimuli. Here, we comprehensively explore the intricate molecular and cellular mechanisms that underpin trained immunity, encompassing epigenetic inheritance, metabolic reprogramming, and transcriptional rewiring. Its dual roles are highlighted in health and disease. On one hand, it bolsters host defense against a broad spectrum of pathogens from bacteria to viruses, and enhances vaccine efficacy through heterologous protection. On the other hand, its dysregulation contributes to infection, inflammation, and cancer progression. As for the promising opportunities on therapeutic intervention, the challenges in precisely modulating trained immunity are tackled to offer a holistic perspective on the dynamically evolving field.

Natural and trained innate immunity against Mycobacterium tuberculosis

1448 Altered myeloid memory function by BMP signaling in breast cancer bone metastases

Immune memory has long been thought to be restricted to the adaptive immune system of vertebrates. However, several lines of evidence have changed our understanding of immune memory and have shattered the strict separation between innate and adaptive immunity. In vertebrates, a form of innate immunity that is called ‘trained immunity’ has been intensively studied for over a decade. For more than two decades, studies in plants and an increasing number of invertebrate taxa have clearly demonstrated that these organisms also possess immune memory, despite the absence of an adaptive immune system. These phenomena are mostly known as ‘immune priming’. The mechanistic underpinnings of immune priming vary across taxa and may or may not partially include the epigenetic and metabolic mechanisms involved in trained immunity. Here, we offer an evolutionary perspective on immune priming, uniquely integrating key aspects across plants and invertebrates for the first time. As a basis, we provide a conceptual clarification regarding the terms trained immunity and immune priming and give a brief overview of these phenomena across taxa. We then analyze which processes of immune priming share potentially evolutionary conserved epigenetic and metabolic processes with trained immunity and explore signaling processes involved in immune priming. We discuss the aspect of specificity as one of the key defining criteria for immune memory and incorporate the potential role of soil and gut microbiota for acquiring innate immune memory in plants and invertebrates. Finally, we argue that immune priming has enormous potential for application beyond the medical field when involving the protection against parasites and pathogens in agriculture and aquaculture.