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Two recent papers from the laboratory of Professor Ming Li demonstrate that inhibition of transforming growth factor specifically in CD4 SP + sp T cells can suppress tumor growth through an unanticipated mechanism. In their paper, Liu I et al i .5 provide an unanticipated explanation for why inhibition of TGF signaling in CD4 SP + sp T cells inhibits tumor growth. Strikingly, this effect was I completely independent i of CD8 SP + sp T cells, suggesting that TGF inhibition in CD4 SP + sp T cells acts through a mechanism unrelated to a T-helper cell-mediated promotion of CD8 SP + sp T-cell immunity. [Extracted from the article]

As the prevalence of viral infection in body, human T‐cell leukemia virus type 1 (HTLV‐1) is receiving increasing attention. Research on the corresponding virus models is of great significance to tackle the challenges of understanding HTLV‐1 development and treatment. This paper focuses on the dynamic analysis for a stochastic model with nonlinear cytotoxic T lymphocyte (CTL) response, which is driven by Ornstein–Uhlenbeck (OU) process to model the progression of HTLV‐1 in vivo. Rich dynamic behaviors such as the extinction of infected CD4+ T cells (ITCs), stationary distribution (SD), probability density, and finite‐time stability (FTS) of the model are established to reveal the interaction of cell populations. The optimal therapeutic strategy based on the cost‐benefit viewpoint is further obtained. Finally, illustrative numerical simulations are represented to corroborate the effectiveness of treatment and the ambient perturbation's impact that strengthening the noise strength can lead to rapid virus clearance. [ABSTRACT FROM AUTHOR]

This paper explores the dynamics analysis of a human immunodeficiency virus (HIV) model with saturated cytotoxic T lymphocyte (CTL) immune response and Beddington–DeAngelis infection rate. There are two time delays in the model to describe the time needed for infection of cell and CTL immune response generation, respectively. We obtain two thresholds and three possible equilibria from the model. By analyzing the corresponding characteristic equations, we study the stabilities of equilibrium and the effect of delays on CTL immune response. The results indicate that when immune delay is present, the steady state of equilibrium is disrupted and leads to a Hopf bifurcation. Finally, we use sensitivity analyses to show the effect of parameters on thresholds and numerical simulations to illustrate the theoretical results. [ABSTRACT FROM AUTHOR]

Malignant glioma is an aggressive primary brain tumor. Due to its location, the interactions of glioma and the immune system are complex. We start this paper by proposing a simple mathematical model that describes the interaction among glioma cells, microglia and cytotoxic T lymphocytes (CTLs). The existence and stability conditions of the equilibrium points are analyzed. Numerical results showed that neither microglia nor CTLs has the ability to eradicate the tumor. As a result, we extend the model by including the chemotherapeutic agent. The model has six equilibrium points, and one of these points represents a cured state. Through local stability, we found a range of values for the infusion rate that guarantees the elimination of glioma, as well as preventing the glioma from reoccurring. [ABSTRACT FROM AUTHOR]

Immunotherapy using immune checkpoint inhibitors (ICIs) has shown superior efficacy compared with conventional chemotherapy in certain cancer types, establishing immunotherapy as the fourth standard treatment alongside surgical intervention, chemotherapy, and radiotherapy. In cancer immunotherapy employing ICIs, CD8‐positive cytotoxic T lymphocytes are recognized as the primary effector cells. For effective clinical outcomes, it is essential that the targeted cancer cells express HLA class I molecules to present antigenic peptides derived from the tumor. However, cancer cells utilize various mechanisms to downregulate or lose HLA class I molecules from their surface, resulting in evasion from immune surveillance. Correlations between prognosis and the integrity of HLA class I molecules expressed by cancer cells have been consistently found across different types of cancer. This paper provides an overview of the regulatory mechanisms of HLA class I molecules and their role in cancer immunotherapy, with a particular emphasis on the significance of utilizing pathological tissues to evaluate HLA class I molecules expressed in cancer cells. [ABSTRACT FROM AUTHOR]

Vitiligo is caused by an autoimmune reaction against melanocytes leading to melanocyte loss. The cause of vitiligo is an interaction between genetic susceptibility and environmental factors. Both the adaptive immune system—through cytotoxic CD8+ T cells and melanocyte specific antibodies—and the innate immune system are involved in these immune processes in vitiligo. While recent data stressed the importance of innate immunity in vitiligo, the question remains why vitiligo patients' immune response becomes overly activated. Could a long‐term increase in innate memory function, described as trained immunity after vaccination and in other inflammatory diseases, play a role as an enhancer and continuous trigger in the pathogenesis of vitiligo? After exposure to certain stimuli, innate immune system is able to show an enhanced immunological response to a secondary trigger, indicating a memory function of the innate immune system, a concept termed trained immunity. Trained immunity is regulated by epigenetic reprogramming, including histone chemical modifications and changes in chromatin accessibility that cause sustained changes in the transcription of specific genes. In responses to an infection, trained immunity is beneficial. However, there are indications of a pathogenic role of trained immunity in inflammatory and autoimmune diseases, with monocytes presenting features of a trained phenotype, resulting in increased cytokine production, altered cell metabolism through mTOR signaling, and epigenetic modifications. This hypothesis paper focusses on vitiligo studies that have shown these indications, suggesting the involvement of trained immunity in vitiligo. Future studies focusing on metabolic and epigenetic changes in innate immune cell populations in vitiligo could help in elucidating the potential role of trained immunity in vitiligo pathogenesis. [ABSTRACT FROM AUTHOR]

Recent researches show that virus‐to‐cell infection and cell‐to‐cell transmission are two HIV infection modes. In this paper, we propose a delayed HIV infection model including both virus‐to‐cell infection and cell‐to‐cell transmission and cytotoxic T lymphocyte immune response. The time delay describes the phenomenon between viral entry and viral production. We show the nonnegativity and boundedness of solution, obtain the steady states, and prove local asymptotic stability of the steady states. Then the optimal control problem with antiretroviral therapy and pharmacological delay is posed. We establish and analyze two types of objective functions: one is linear control and the other is quadratic control. Numerical simulations have been performed to verify the stability of steady states and show the optimal control strategies and the effects of control on cells concentration by Matlab and Lingo. [ABSTRACT FROM AUTHOR]

Severe acute respiratory syndrome coronavirus 2 (SARS‐CoV‐2) is uncontrollably spread all over the world. The host immune responses strongly try to confront it with all the potential cells and cytokines. With chronically condition of SARS‐CoV‐2, natural killer cells and T cells become exhausted and decreasing their count leads to lymphopenia. Inability to eradicate the infected organ makes hyperinitiation of the immune system, which releases the excessive inflammatory cytokines to compensate the exhausted one as well as the low lymphocytes counts; it consequently leads to the cytokine storm syndrome. These mechanisms and the potential therapeutic targeting are discussed in this paper. [ABSTRACT FROM AUTHOR]

In this paper, a periodic stochastic human immunodeficiency virus (HIV) model with distributed delay and cytotoxic T lymphocytes (CTL) immune response is investigated. First, by It ô's formula, we show that the solution with any positive initial value is global and positive. Then, by the stochastic comparison theorem, we obtain the sufficient conditions guaranteeing the existence and global attractivity of infection‐free periodic solution. Furthermore, we discuss the existence of the infective periodic solution by Has'minskii theory. Finally, numerical examples are given to illustrate the results. [ABSTRACT FROM AUTHOR]

This paper studies an (n+4)‐dimensional nonlinear virus dynamics model that characterizes the interactions of the viruses, susceptible host cells, n‐stages of infected cells, B cells and cytotoxic T lymphocyte (CTL) cells. Both viral and cellular infections have been incorporated into the model. The infected‐susceptible and virus‐susceptible infection rates as well as the generation and removal rates of all compartments are described by general nonlinear functions. Five threshold parameters are computed, which insure the existence of the equilibria of the model under consideration. A set of conditions on the general functions has been established, which is sufficient to investigate the global dynamics of the model. The global asymptotic stability of all equilibria is proven by utilizing Lyapunov function and LaSalle's invariance principle. The theoretical results are illustrated by numerical simulations of the model with specific forms of the general functions. [ABSTRACT FROM AUTHOR]

Direct cell‐to‐cell transmission of HIV‐1 is a more efficient means of virus infection than virus‐to‐cell transmission. In this paper, we incorporate both these transmissions into an HIV‐1 virus model with nonlinear general incidence rate, intracellular delay, and cytotoxic T lymphocyte (CTL) immune responses. This model admits three types of equilibria: infection‐free equilibrium, CTL‐inactivated equilibrium, and CTL‐activated equilibrium. By using Lyapunov functionals and LaSalle invariance principle, it is verified that global threshold dynamics of the model can be explicitly described by the basic reproduction numbers. [ABSTRACT FROM AUTHOR]

The naked mole rat (Heterocephalus glaber, NMR) is a rodent with exceptional longevity, low rates of age‐related diseases and spontaneous carcinogenesis. The NMR represents an attractive animal model in longevity and cancer research, but there are no NMR‐specific antibodies available to study its immune system with respect to age‐ and cancer‐related questions. Substantial homology of major NMR immune cell markers with those of Guinea pig, human and, to a lesser extent, mouse and rat origin are implicated for the existence of immunological cross‐reactivity. We identified 10 antibodies recognising eight immunophenotypic markers expressed on the NMR's T and B lymphocytes, macrophages/monocytes and putative haematopoietic precursors and used them for an immunophenotyping of leukocyte subsets of peripheral blood, spleen and bone marrow samples. Overall, we found that the leukocyte composition of NMR peripheral blood is comparable to that of mice. Notably, the frequency of cytotoxic T cells was found to be lower in the NMR compared to corresponding mouse tissues and human blood. Antibodies used in the present paper are available either commercially or from the scientific community and will provide new opportunities for the NMR as a model system in ageing‐ and cancer‐related research areas. [ABSTRACT FROM AUTHOR]

In this paper, we develop a diffusive and delayed hepatitis B virus (HBV) infection model, which incorporates both virus‐to‐cell and cell‐to‐cell transmissions along with cytotoxic T lymphocyte (CTL) immune response. Two threshold parameters ℜ0$$ {\mathfrak{\Re}}_0 $$ (basic reproduction number) and ℜ1$$ {\mathfrak{\Re}}_1 $$ (immune response reproduction number) are defined, which determine the dynamic behavior of the model. Employing the approach of Lyapunov functionals, we show that the infection‐free steady state is globally asymptotically stable when ℜ0≤1$$ {\mathfrak{\Re}}_0\le 1 $$; the immune‐free infected steady state is globally asymptotically stable when ℜ1≤1<ℜ0$$ {\mathfrak{\Re}}_1\le 1<{\mathfrak{\Re}}_0 $$; and the immune‐present steady state is globally asymptotically stable when ℜ0>1,ℜ1>1$$ {\mathfrak{\Re}}_0>1,{\mathfrak{\Re}}_1>1 $$, and φ(I)=I$$ \varphi (I)=I $$. We perform the sensitivity and uncertainly analysis on ℜ0$$ {\mathfrak{\Re}}_0 $$ with respect to parameters and find that the most important parameter that drives the HBV infection is the mortality of HBV DNA capsids. Moreover, the theoretical results are supported with numerical simulations. [ABSTRACT FROM AUTHOR]

The goal of this paper is to investigate the dynamical behavior of a general nonlinear delayed viral infection model with cytotoxic T lymphocyte (CTL) immune response. The intrinsic growth rate of uninfected hepatocytes, incidence rate of infection, removal rate of infected hepatocytes and capsids, production and removal rate of viruses, activation rate of CTLs, and decay rate of CTLs are given by general nonlinear functions with a set of conditions on these general nonlinear functions, which make the analysis of the model more difficult. The global threshold dynamics with respect to the reproduction numbers for viral infection R0 and for CTL immune response R1 have been presented by constructing suitable Lyapunov functionals. Numerical simulations are carried out for a model with specific forms of the general functions to confirm the theoretical results and show that both the numerical and theoretical results are consistent. [ABSTRACT FROM AUTHOR]

Abstract: Alemtuzumab is a humanized mAb targeted to CD52. Alemtuzumab is highly immunosuppressive with the ability to deplete T and B cells (in addition to other immune cell lines). A growing understanding of the PKs, dosing, and timing of administration of alemtuzumab has allowed for the study of its use as a conditioning agent for allogeneic HCT. The highly immunosuppressive properties of the drug are particularly appealing in the setting of non‐malignant HCT, where GVHD provides no clinical benefit and relapse of malignancy is not applicable. In addition, the degree of immune suppression achieved with alemtuzumab has allowed for a reduction in the intensity of myeloablative cytotoxic agents included in some HCT conditioning regimens, allowing for fewer acute and late toxicities. This review paper will provide a comprehensive summary of the mechanism of action, PKs, dosing, and timing of alemtuzumab, a brief description of its use in various allogeneic HCT protocols for non‐malignant conditions and a summary of the data regarding its use for GVHD therapy. The goal of this review was to provide an understanding as to how alemtuzumab might be safely incorporated into HCT conditioning regimens for children with non‐malignant disease, allowing for expanded access to curative HCT therapy. [ABSTRACT FROM AUTHOR]

In this paper, using the methods of killing tumors and impulsive differential equations, two immunotherapy antitumor models for describing therapies of general tumors and advanced solid tumors are established. By using the theories of impulsive equations, small amplitude perturbation techniques, and the comparison technique, we obtain the conditions which guarantee the global asymptotical stability of the tumor‐eliminated periodic solution and system permanence, when immunotherapy alone is performed. The numerical results of the influences of the impulsive perturbation on the inherent oscillation show rich dynamics, such as period‐doubling bifurcation and chaos. Moreover, the effects of the combination of radiotherapy with immunotherapy on antitumor are obtained, including the threshold value of stability conditions of tumor‐eradication periodic solution when the mixed combination treatment of immunotherapy and radiotherapy is performed. Some numerical simulations for the effects of the timing of radiotherapy application and the timing of injection T cells on the threshold value are performed. Finally, we present some theoretical methods for suppressing the growth of tumors. [ABSTRACT FROM AUTHOR]

In this paper, we formulate a within‐host dynamics model for HIV/HTLV‐I co‐infection under the influence of cytotoxic T lymphocytes (CTLs). The model incorporates silent HIV‐infected CD4+T cells and silent HTLV‐infected CD4+T cells. The model includes two routes of HIV transmission, virus to cell (VTC) and cell to cell (CTC). It also incorporates two modes of HTLV‐I transmission, horizontal transmission via direct CTC contact and vertical transmission through mitotic division of Tax‐expressing HTLV‐infected cells. The model takes into account five types of distributed‐time delays. We analyze the model by proving the nonnegativity and boundedness of the solutions, calculating all possible equilibria, deriving a set of key threshold parameters, and proving the global stability of all equilibria. The global asymptotic stability of all equilibria is established by utilizing Lyapunov function and LaSalle's invariance principle. We present numerical simulations to justify the applicability and effectiveness of the theoretical results. In addition, we discuss the effect of HTLV‐I infection on the HIV dynamics and vice versa. [ABSTRACT FROM AUTHOR]

In this paper, the dynamics of stochastic human T‐cell leukemia virus type I (HTLV‐I) infection model with cytotoxic T lymphocyte (CTL) immune response is investigated. First, we show that the stochastic model exists as a unique positive global solution originating from the positive initial value. Second, we demonstrate that the stochastic model is stochastically permanent and stochastically ultimately bounded for any positive initial value. Third, we establish sufficient conditions for the existence of ergodic stationary distribution of the stochastic model. Fourth, the threshold R0∗ between extinction and persistence of the virus is obtained. Finally, numerical simulations are carried out to illustrate the theoretical results. [ABSTRACT FROM AUTHOR]

According to the latest evidence, the microbial metabolite Urolithin A (UA), known for its role in promoting cellular health, modulates CD8+ T cell‐mediated antitumor activity. However, the direct target protein of UA and its underlying mechanism remains unclear. Here, this research identifies ERK1/2 as the specific target crucial for UA‐mediated CD8+ T cell activation. Even at low doses, UA markedly enhances the persistence and effector functions of primary CD8+ cytotoxic T lymphocytes (CTLs) and human chimeric antigen receptor (CAR) T cells both in vitro and in vivo. Mechanistically, UA interacts directly with ERK1/2 kinases, enhancing their activation and subsequently facilitating T cell activation by engaging ULK1. The UA‐ERK1/2‐ULK1 axis promotes autophagic flux in CD8+ CTLs, enhancing cellular metabolism and maintaining reactive oxygen species (ROS) levels, as evidenced by increased oxygen consumption and extracellular acidification rates. UA‐treated CD8+ CTLs also display elevated ATP levels and enhanced spare respiratory capacity. Overall, UA activates ERK1/2, inducing autophagy and metabolic adaptation, showcasing its potential in tumor immunotherapy and interventions for diseases involving ERKs. [ABSTRACT FROM AUTHOR]

Personalized cancer vaccines based on resected tumors from patients is promising to address tumor heterogeneity to inhibit tumor recurrence or metastasis. However, it remains challenge to elicit immune activation due to the weak immunogenicity of autologous tumor antigens. Here, a hybrid membrane cancer vaccine is successfully constructed by membrane fusion to enhance adaptive immune response and amplify personalized immunotherapy, which formed a codelivery system for autologous tumor antigens and immune adjuvants. Briefly, the functional hybrid vesicles (HM‐NPs) are formed by hybridizing ginseng‐derived extracellular vesicles‐like particles (G‐EVLPs) with the membrane originated from the resected autologous tumors. The introduction of G‐EVLPs can enhance the phagocytosis of autologous tumor antigens by dendritic cells (DCs) and facilitate DCs maturation through TLR4, ultimately activating tumor‐specific cytotoxic T lymphocytes (CTLs). HM‐NPs can indeed strengthen specific immune responses to suppress tumors recurrence and metastasis including subcutaneous tumors and orthotopic tumors. Furthermore, a long‐term immune protection can be obtained after vaccinating with HM‐NPs, and prolonging the survival of animals. Overall, this personalized hybrid autologous tumor vaccine based on G‐EVLPs provides the possibility of mitigating tumor recurrence and metastasis after surgery while maintaining good biocompatibility. [ABSTRACT FROM AUTHOR]

This article explores the molecular characteristics and immune microenvironments of secondary radiation-exposed rectal cancers (SRCs) compared to primary rectal cancers (PRCs). The study used single-cell transcriptomic sequencing to analyze the cell type-specific profiles of 18 SRCs and identified distinct differences in copy number variation and immune cell composition between SRCs and PRCs. The findings suggest that oncogene amplification and the activation of Treg cells may promote the progression of SRCs, while the emergence of neutrophils and activation of macrophages contribute to the immune microenvironment of SRCs. The study provides valuable insights into the tumorigenesis of SRCs and potential therapeutic strategies. [Extracted from the article]

Immunotherapy targeting PD‐L1 is still ineffective for a wide variety of tumors with high unpredictability. Deploying combined immunotherapy with alternative targeting is practical to overcome this therapeutic resistance. Here, the deficiency of serine‐threonine kinase STK24 is observed in tumor cells causing substantial attenuation of tumor growth in murine syngeneic models, a process relying on cytotoxic CD8+ T and NK cells. Mechanistically, STK24 in tumor cells associates with and directly phosphorylates AKT at Thr21, which promotes AKT activation and subsequent PD‐L1 induction. Deletion or inhibition of STK24, by contrast, blocks IFN‐γ‐mediated PD‐L1 expression. Various murine models indicate that in vivo silencing of STK24 can significantly enhance the efficacy of the anti‐PD‐1 blockade strategy. Elevated STK24 levels are observed in patient specimens in multiple tumor types and inversely correlated with intratumoral infiltration of cytotoxic CD8+ T cells and with patient survival. The study collectively identifies STK24 as a critical modulator of antitumor immunity, which engages in AKT and PD‐L1/PD‐1 signaling and is a promising target for combined immunotherapy. [ABSTRACT FROM AUTHOR]

The liver is the most tolerogenic of transplanted organs. However, the mechanisms underlying liver transplant tolerance are not well understood. The comparison between liver transplantation tolerance and heart/kidney transplantation rejection will deepen our understanding of tolerance and rejection in solid organs. Here, we built a mouse model of liver, heart and kidney allograft and performed single-cell RNA sequencing of 66,393 cells to describe the cell composition and immune cell interactions at the early stage of tolerance or rejection. We also performed bulk RNA-seq of mouse liver allografts from Day 7 to Day 60 posttransplantation to map the dynamic transcriptional variation in spontaneous tolerance. The transcriptome of lymphocytes and myeloid cells were characterized and compared in three types of organ allografts. Cell-cell interaction networks reveal the coordinated function of Kupffer cells, macrophages and their associated metabolic processes, including insulin receptor signalling and oxidative phosphorylation in tolerance induction. Cd11b+ dendritic cells (DCs) in liver allografts were found to inhibit cytotoxic T cells by secreting anti-inflammatory cytokines such as Il10. In summary, we profiled single-cell transcriptome analysis of mouse solid organ allografts. We characterized the immune microenvironment of mouse organ allografts in the acute rejection state (heart, kidney) and tolerance state (liver). [ABSTRACT FROM AUTHOR]

A two‐dimensional tumor‐immune model with the time delay of the adaptive immune response is considered in this paper. The model is designed to account for the interaction between cytotoxic T lymphocytes (CTLs) and cancer cells on the surface of a solid tumor. The model considers the surface growth as a major growth pattern of solid tumors in order to describe the existence of necrotic kernels. The qualitative analysis shows that the immune‐free equilibrium is unstable, and the behavior of positive equilibrium is closely related to the ratio of the immune killing rate to tumor volume growth rate. The positive equilibrium is locally asymptotically stable when the ratio is smaller than a critical value. Otherwise, the occurrence of the delay‐driven Hopf bifurcation at the positive equilibrium is proved. Applying the center manifold reduction and normal form method, we obtain explicit formulas to determine the properties of the Hopf bifurcation. The global continuation of a local Hopf bifurcation is investigated based on the coincidence degree theory. The results reveal that the time of the adaptive immune system taken to response to tumors can lead to oscillation dynamics. We also carry out detailed numerical analysis for parameters and numerical simulations to illustrate our qualitative analysis. Numerically, we find that shorter immune response time can lead to longer patient survival time, and the period and amplitude of a stable periodic solution increase with the increasing immune response time. When CTLs recruitment rate and death rate vary, we show how the ratio of the immune killing rate to tumor volume growth rate and the first bifurcation value change numerically, which yields further insights to the tumor‐immune dynamics. [ABSTRACT FROM AUTHOR]

Hepatocellular carcinoma (HCC) is one of the leading causes of cancer‐related death worldwide. Hepatectomy remains the first‐line treatment for patients with resectable HCC. However, the reported recurrence rate of HCC at 5 years after surgery is between 50% and 70%. Tumor‐related factors, including tumor size, number and differentiation, and underlying liver disease are well‐known risk factors for recurrence after treatment. In addition to tumor‐related factors, ever‐increasing amounts of studies are finding that the tumor microenvironment also plays an important role in the recurrence of HCC, including systemic inflammatory response and immune regulation. Based on this, some inflammatory and immune markers were used in predicting postoperative cancer recurrence. These include neutrophil‐to‐lymphocyte ratio, platelet‐to‐lymphocyte ratio, cytotoxic T cells, and regulatory T cells, among others. In this review, we summarized the inflammatory and immune markers that affect recurrence after HCC resection in order to provide direction for adjuvant therapy after HCC resection and ultimately achieve the goal of reducing recurrence. [ABSTRACT FROM AUTHOR]

Photodynamic therapy (PDT) has been widely employed in tumor treatment due to its effectiveness. However, the tumor hypoxic microenvironment which is caused by abnormal vasculature severely limits the efficacy of PDT. Furthermore, the abnormal vasculature has been implicated in the failure of immunotherapy. In this study, a novel nanoparticle denoted as Combo‐NP is introduced, composed of a biodegradable NIR II fluorescent pseudo‐conjugate polymer featuring disulfide bonds within its main chain, designated as TPA‐BD, and the vascular inhibitor Lenvatinib. Combo‐NP exhibits dual functionality by not only inducing cytotoxic reactive oxygen species (ROS) to directly eliminate tumor cells but also eliciting immunogenic cell death (ICD). This ICD response, in turn, initiates a robust cascade of immune reactions, thereby augmenting the generation of cytotoxic T lymphocytes (CTLs). In addition, Combo‐NP addresses the issue of tumor hypoxia by normalizing the tumor vasculature. This normalization process enhances the efficacy of PDT while concurrently fostering increased CTLs infiltration within the tumor microenvironment. These synergistic effects synergize to potentiate the photodynamic‐immunotherapeutic properties of the nanoparticles. Furthermore, when combined with anti‐programmed death‐ligand 1 (PD‐L1), they showcase notable inhibitory effects on tumor metastasis. The findings in this study introduce an innovative nanomedicine strategy aimed at triggering systemic anti‐tumor immune responses for the treatment of Uveal melanoma. [ABSTRACT FROM AUTHOR]

Immune cells have an uncertain function during the progression of extranodal natural killer/T‐cell lymphoma (ENKTL). The present study determined the distribution, phenotype, and clinical significance of B lymphocytes in ENKTL. Immunohistochemistry indicated high infiltration of CD20+ B lymphocytes in the tumour tissues of 40% of the patients, and that a high infiltration correlated with better overall survival. Moreover, B lymphocytes had an active mature phenotype in situ and suppressed the proliferation of ENKTL cells in vitro. These results suggest that tumour infiltration of CD20+ B lymphocytes may be a new prognostic indicator for patients with ENKTL. [ABSTRACT FROM AUTHOR]

In this paper, a mathematical model for HIV-1 infection with antibody, cytotoxic T-lymphocyte immune responses and Beddington-DeAngelis functional response is investigated. The stability of the infection-free and infected steady states is investigated. The basic reproduction number R0 is identified for the proposed system. If R0 < 1, then there is an infection-free steady state, which is locally asymptotically stable. Further, the infected steady state is locally asymptotically stable for R0 > 1 in the absence of immune response delay. We use Nyquist criterion to estimate the length of the delay for which stability continues to hold. Also the existence of the Hopf bifurcation is investigated by using immune response delay as a bifurcation parameter. Numerical simulations are presented to justify the analytical results. Copyright © 2014 John Wiley & Sons, Ltd. [ABSTRACT FROM AUTHOR]

T‐cell large granular lymphocyte (T‐LGL) leukaemia is characterized by a clonal proliferation of cytotoxic T cells and is frequently associated with rheumatoid arthritis. Sera from some LGL leukaemia patients react to a portion of the human T‐cell leukaemia virus (HTLV‐1/2) transmembrane envelope protein, BA21, although HTLV‐1/2 infection is rare in LGL leukaemia patients. Here we show that family members, including spouses, of an LGL leukaemia patient had elevated LGL counts, BA21 reactivity and, additionally, recognition of HIV‐1 gp41. Thus, both LGL leukaemia patients and clinically normal contacts sharing the same environment have evidence of exposure to a retrovirus. [ABSTRACT FROM AUTHOR]

The acute pulmonary responses after exposure to sulfur and nitrogen mustards are well documented whereas the late pulmonary effects are not. With a novel focus on the immune system this paper investigate whether late phase pulmonary effects developed in rats exposed to the nitrogen mustard melphalan are linked to the acute responses and whether the reactions are genetically regulated. The DA rat strain was used to establish a lung exposure model. Five other inbred rat strains (PVG, PVG.1AV1, LEW, WF and F344) were compared within the model at selected time points. All rat strains displayed a biphasic pattern of leukocyte infiltration in the lungs, dominated by neutrophils 2 days after exposure and a second peak dominated by macrophages 29 days after exposure. The number of macrophages was higher in the DA rat compared with the other strains. The infiltration of lymphocytes in the lungs varied in both time of appearance and magnitude between strains. The quantity of collagen deposition in the lungs varied between strains at day 90; LEW and WF displayed high collagen content which coincided with an increased level of cytotoxic T cells. LEW further displayed an increased number of T helper cells and natural killer (NK) T cells in the lungs. The results in this study suggest there is a link between the development of lung fibrosis and high cytotoxic cell responses and that there is a genetic influence, as there are variations in acute and late adverse reactions between rat strains in both timing and magnitude. Copyright © 2013 John Wiley & Sons, Ltd. [ABSTRACT FROM AUTHOR]

Summary The bacterial superantigen exotoxins of Staphylococcus aureus and Streptococcus pyogenes are potent stimulators of polyclonal T-cell proliferation. They are the causes of toxic shock syndrome but also induce CD25+ FOXP3+ regulatory cells in the CD4 compartment. Several studies have recently described different forms of antigen-induced regulatory CD8+ T cells in the context of inflammatory diseases and chronic viral infections. In this paper we show that bacterial superantigens are potent inducers of human regulatory CD8+ T cells. We used four prototypic superantigens of S. aureus (toxic shock syndrome toxin-1 and staphylococcal enterotoxin A) and Str. pyogenes (streptococcal pyrogenic exotoxins A and K/L). At concentrations below 1 ng/ml each toxin triggers concentration-dependent T-cell receptor Vβ-specific expression of CD25 and FOXP3 on CD8+ T cells. This effect is independent of CD4+ T-cell help but requires antigen-presenting cells for maximum effect. The cells also express the activation/regulatory markers cytotoxic T-lymphocyte antigen-4 and glucocorticoid-induced tumour necrosis factor receptor-related protein and skin homing adhesins CD103 and cutaneous lymphocyte-associated antigen. Superantigen-induced CD25+ FOXP3+ CD8+ T cells were as potent as freshly prepared naturally occurring CD4+ regulatory T cells in suppressing proliferation of CD4+ CD25− T cells in response to anti-CD3 stimulation. Although superantigen-induced CD8+ CD25+ FOXP3+ express interleukin-10 and interferon-γ their suppressive function is cell contact dependent. Our findings indicate that regulatory CD8+ T cells may be a feature of acute bacterial infections contributing to immune evasion by the microbe and disease pathogenesis. The presence and magnitude of regulatory CD8+ T-cell responses may represent a novel biomarker in such infections. Superantigen-induced regulatory CD8+ T cells also have therapeutic potential. [ABSTRACT FROM AUTHOR]

The Genotype List (GL) String grammar for reporting HLA and Killer‐cell Immunoglobulin‐like Receptor (KIR) genotypes in a text string was described in 2013. Since this initial description, GL Strings have been used to describe HLA and KIR genotypes for more than 40 million subjects, allowing these data to be recorded, stored and transmitted in an easily parsed, text‐based format. After a decade of working with HLA and KIR data in GL String format, with advances in HLA and KIR genotyping technologies that have fostered the generation of full‐gene sequence data, the need for an extension of the GL String system has become clear. Here, we introduce the new GL String delimiter "?," which addresses the need to describe ambiguity in assigning a gene sequence to gene paralogs. GL Strings that do not include a "?" delimiter continue to be interpreted as originally described. This extension represents version 1.1 of the GL String grammar. [ABSTRACT FROM AUTHOR]

A key phenomenon in cancer is the establishment of a highly immunosuppressive tumour microenvironment (TME). Despite advances in immunotherapy, where the purpose is to induce tumour recognition and hence hereof tumour eradication, the majority of patients applicable for such treatment still fail to respond. It has been suggested that high immunological activity in the tumour is essential for achieving effective response to immunotherapy, which therefore have led to exploration of strategies that triggers inflammatory pathways. Here activation of the stimulator of interferon genes (STING) signalling pathway has been considered an attractive target, as it is a potent trigger of pro‐inflammatory cytokines and types I and III interferons. However, immunotherapy combined with targeted STING agonists has not yielded sustained clinical remission in humans. This suggests a need for exploring novel adjuvants to improve the innate immunological efficacy. Here, we demonstrate that extracellular vesicles (EVs), derived from activated CD4+ T cells (T‐EVs), sensitizes macrophages to elevate STING activation, mediated by IFNγ carried on the T‐EVs. Our work support that T‐EVs can disrupt the immune suppressive environment in the tumour by reprogramming macrophages to a pro‐inflammatory phenotype, and priming them for a robust immune response towards STING activation. [ABSTRACT FROM AUTHOR]

Protein subunit vaccines have been used as prophylactic vaccines for a long time. The well‐established properties of these vaccines make them the first choice for the coronavirus disease 2019 (COVID‐19) outbreak. However, it is not easy to develop a protein vaccine that induces cytotoxic T lymphocyte responses and requires a longer time for manufacturing, which limits the usage of this vaccine type. Here, we report the combination of a recombinant spike (S)‐trimer protein with a DNA vaccine‐encoded S protein as a novel COVID‐19 vaccine. The recombinant S protein was formulated with different adjuvants and mixed with the DNA plasmid before injection. We found that the recombinant S protein formulated with the adjuvant aluminum hydroxide and mixed with the DNA plasmid could enhance antigen‐specific antibody titers, neutralizing antibody titers. We further evaluated the IgG2a/IgG1 isotype and cytokine profiles of the specific boosted T‐cell response, which indicated that the combined vaccine induced a T‐helper 1 cell‐biased immune response. Immunized hamsters were challenged with severe acute respiratory syndrome coronavirus 2, and the body weight of the hamsters that received the recombinant S protein with aluminum hydroxide and/or the DNA plasmid was not reduced. Alternatively, those that received control or only the DNA plasmid immunization were reduced. Interestingly, after the third day of the viral load in the lungs, the viral challenge could not be detected in hamsters immunized with the recombinant S protein in aluminum hydroxide mixed with DNA (tissue culture infectious dose < 10). The viral load in the lungs was 109, 106, and 107 for the phosphate‐buffered saline, protein in aluminum hydroxide, and DNA‐only immunizations, respectively. These results indicated that antiviral mechanisms neutralizing antibodies play important roles. Furthermore, we found that the combination of protein and DNA vaccination could induce relatively strong CD8+ T‐cell responses. In summary, the protein subunit vaccine combined with a DNA vaccine could induce strong CD8+ T‐cell responses to increase antiviral immunity for disease control. [ABSTRACT FROM AUTHOR]

Citrullination and homocitrullination are stress induced post‐translational modifications (siPTMs) which can be recognized by T cells. Peripheral blood mononuclear cells isolated from healthy donors and rheumatoid arthritis (RA) patients were stimulated with nine siPTM‐peptides. CD45RA/CD45RO depletion was employed to determine if peptide‐specific responses are naïve or memory. Human leucocyte antigen (HLA)‐DP4 and HLA‐DR4 transgenic mice were immunized with siPTM‐peptides and immune responses were determined with ex vivo ELISpot assays. The majority (24 out of 25) of healthy donors showed CD4 T cell‐specific proliferation to at least 1 siPTM‐peptide, 19 to 2 siPTM‐peptides, 14 to 3 siPTM‐peptides, 9 to 4 siPTM‐peptides, 6 to 5 siPTM‐peptides and 4 to 6 siPTM‐peptides. More donors responded to Vim28‐49cit (68%) and Bip189‐208cit (75%) compared with Vim415‐433cit (33%). In RA patients, the presentation of citrullinated epitopes is associated with HLA‐SE alleles; however, we witnessed responses in healthy donors who did not express the SE allele. The majority of responding T cells were effector memory cells with a Th1/cytotoxic phenotype. Responses to Vim28‐49cit and Eno241‐260cit originated in the memory pool, while the response to Vim415‐433cit was naïve. In the HLA‐DP4 and HLA‐DR4 transgenic models, Vim28cit generated a memory response. Peptide‐specific T cells were capable of Epstein–Barr virus transformed lymphoblastoid cell line recognition suggesting a link with stress due to infection. These results suggest siPTM‐peptides are presented under conditions of cellular stress and inflammation and drive cytotoxic CD4 T cell responses that aid in the removal of stressed cells. The presentation of such siPTM‐peptides is not restricted to HLA‐SE in both humans and animal models. [ABSTRACT FROM AUTHOR]

Anticancer drug‐mediated induction of immunogenic cell death (ICD) blocks metastasis or recurrence in cancer cells by promoting specific immune activity against cancer antigens. However, this strategy has failed to afford adequate treatment efficiency. Overcoming the failure of ICD‐mediated cancer therapy, lipid nanoparticles (LNPs) containing cancer cell surface proteins are synthesized using sonication and extrusion without microfluidics. In addition, these LNPs are decorated with high‐mobility group box 1 protein and calreticulin, indicators of ICD, and named artificial ICD LNPs (AiLNPs). Administration of AiLNPs effectively targets dendritic cells (DCs) and induces DC activation in mice. Moreover, treating CT‐26 tumor‐bearing mice with AiLNPs inhibits tumor growth by inducing CT‐26 antigen‐specific T‐cell immunity. Furthermore, AiLNPs containing Lewis lung carcinoma (LLC1) membrane proteins can prevent metastatic LLC1 tumor growth in the lung via LLC1 antigen‐specific T‐cell activation. Finally, AiLNPs synthesized with human breast cancer membrane proteins activate DC‐mediated antigen‐specific T‐cell immunity, effectively killing tumor cells. Therefore, AiLNPs are expected to be developed as a patient‐specific cancer treatment to prevent cancer recurrence and metastasis. [ABSTRACT FROM AUTHOR]

Summary: Adult T‐cell leukaemia/lymphoma (ATL) is an aggressive malignancy of peripheral T cells caused by human T‐cell lymphotropic virus type‐1 (HTLV‐1). Tax is the most important regulatory protein for HTLV‐1. We aimed to reveal a unique amino acid sequence (AA) of complementarity‐determining region 3 (CDR3) of the T‐cell receptor (TCR)β and TCRα chains of HLA‐A*02:01‐restricted Tax11–19‐specific cytotoxic T cells (Tax‐CTLs). The gene expression profiles (GEP) of Tax‐CTLs were assessed by the next‐generation sequence (NGS) method with SMARTer technology. Tax‐CTLs seemed to be oligoclonal, and their gene compositions were skewed. The unique motifs of 'DSWGK' in TCRα and 'LAG' in TCRβ at CDR3 were observed in almost all patients. Tax‐CTL clones harbouring the 'LAG' motif with BV28 had a higher binding score than those without either of them, besides a higher binding score associated with longer survival. Tax‐CTLs established from a single cell showed killing activities against Tax‐peptide‐pulsed HLA‐A2+ T2 cell lines. GEP of Tax‐CTLs revealed that genes associated with immune response activity were well preserved in long‐term survivors with stable status. These methods and results can help us better understand immunity against ATL, and should contribute to future studies on the clinical application of adoptive T‐cell therapies. [ABSTRACT FROM AUTHOR]

PF13: EV Heterogeneity 1 Chairs: Michael Harding, Andre Gorgens Location: Hall 4A 16:00 - 18:00 PF13.08 Comparisons of Tetraspanin profile of Extracellular Vesicles-derived from Sarcoma Cel... Thitikan Jirakittisonthon SP 1 sp ; Orman L. Snyder SP 2 sp ; Hong He SP 3 sp ; Mark Weiss SP 1 sp I SP 1 sp Kansas State University, Manhattan, USA; SP 2 sp Kansas State University, Topeka, USA; SP 3 sp Kansas State University, USA i B Introduction b : Based on Minimum Information for Studies of Extracellular Vesicles 2018 (MISEV 2018), characterization of EVs using transmembrane protein markers is one of the criteria for characterization. B Funding b : Funding was partly provided by NIH grants DP1DK126199, and DP2 EB028110-01 awarded to DGP B keywords b : Engineered EVs, immunomodulation, solid tumors, nonviral gene delivery, tissue nanotransfection PT17.13 Isolation of neuron-derived extracellular vesicles from biological fluids for the dia... Igor V. Kurochkin; Lausonia Ramaswamy I Sysmex Co., Kobe, Japan i B Introduction b : The molecular content of extracellular vesicles (EVs) largely reflects the content of cells of origin and thus analysis of neuron-derived EVs (NDEs) present in plasma offers a possibility of minimally invasive diagnosis of neurological disorders. B keywords b : Extracellular vesicles (EVs), MicroRNAs, Nonalcoholic fatty liver disease, Lipotoxicity, PT09: EVs from Microorganism 1 Chairs: Meta Kuehn, Irma Schabussova Location: Hall 4A 16:45 - 18:45 PT09.14 Examining the role of bacterial extracellular vesicles in host blood pressure regulat... Feiya Shi SP 1 sp ; Rishi Wagle SP 1 sp ; Sriram Ayyaswamy SP 1 sp ; DAVID DURGAN SP 2 sp I SP 1 sp Baylor College of Medicine, USA; SP 2 sp Baylor College of Medicine, Houston, USA i B Introduction b : We have previously demonstrated that disruption of the normal gut microbiota composition, termed gut dysbiosis, is an underlying cause of hypertension (HT). [Extracted from the article]

Effective vaccines have reduced the morbidity and mortality caused by severe acute respiratory syndrome coronavirus‐2 infection; however, the elderly remain the most at risk. Understanding how vaccines generate protective immunity and how these mechanisms change with age is key for informing future vaccine design. Cytotoxic CD8+ T cells are important for killing virally infected cells, and vaccines that induce antigen‐specific CD8+ T cells in addition to humoral immunity provide an extra layer of immune protection. This is particularly important in cases where antibody titers are suboptimal, as can occur in older individuals. Here, we show that in aged mice, spike epitope–specific CD8+ T cells are generated in comparable numbers to younger animals after ChAdOx1 nCoV‐19 vaccination, although phenotypic differences exist. This demonstrates that ChAdOx1 nCoV‐19 elicits a good CD8+ T‐cell response in older bodies, but that typical age‐associated features are evident on these vaccine reactive T cells. [ABSTRACT FROM AUTHOR]

Background: Bladder cancer (BLCA) is one of the most diagnosed cancers in humans worldwide. Recently, immunotherapy has become a main treatment option for BC. However, most BLCA patients do not respond to immune checkpoint inhibitors or relapse after immunotherapy. Therefore, it is very important to identify novel biomarkers for the prediction of immunotherapy response in B patients. Methods: Pancancer single‐cell RNA sequencing (scRNA‐seq) data were used to identify the clusters of CD4+ T cells in the tumour microenvironment (TME). The clinical significance of key CD4+ T‐cell clusters was evaluated based on the survival data of two independent immunotherapy bladder cancer (BLCA) cohorts. We also investigated the function of key clusters of CD4+ T cell in the TME of BC cells in vitro. Results: This study identified two novel exhausted CD4+ T‐cell subpopulations with the expression of PD1hi CD200hi or PD1hi CD200low in BC patients. Moreover, BLCA patients with a high level of PD1hi CD200hi CD4+ exhausted T cell showed immunotherapy resistance. Cell function analysis demonstrated that PD1hi CD200hi CD4+ exhausted T cell can promote epithelial–mesenchymal transition (EMT) and angiogenesis in BLCA cells. In addition, PD1hi CD200hi CD4+ exhausted T cells were shown to communicate with malignant BLCA cells through the GAS6–AXL axis. Finally, we also found that GAS6 expression is upregulated in B cells by METTL3‐mediated m6A modification. Conclusions: PD1hi CD200hi CD4+ exhausted T cell may serve as a novel biomarker for poor prognosis and immunotherapy resistance in B. Targeted inhibitors of PD1hi CD200hi CD4+ exhausted T cells may help improve the efficacy of immunotherapy. [ABSTRACT FROM AUTHOR]

This paper describes the generation, detection and characterization of cytotoxic T lymphocyte activity in vitro and the application of this assay system to various immunological problems. [ABSTRACT FROM AUTHOR]

Chimeric antigen receptor (CAR) T‐cell therapy is an immunotherapy approach that has played a tremendous role in the battle against cancer for years. Since the CAR T lymphocytes are unrestricted‐major histocompatibility complex T lymphocytes, they could identify more targets than natural T cells, resulting in practical and widespread functions. The good prospects of CAR T‐cell therapy in oncology can be additionally applied to treat other diseases such as autoimmune and infectious diseases. CAR‐T cell‐derived immunotherapy for autoimmune disorders can be allocated to CAR‐Tregs and chimeric autoantibody receptor T cells. Other generations of CARs target human immunodeficiency virus (HIV) proteins. In this review, we summarize CAR‐T cell therapies in autoimmune disorders and HIV infection. [ABSTRACT FROM AUTHOR]

High‐frequency mutation of the TP53 tumor suppressor gene is observed in multiple human cancers, which promotes cancer progression. However, the mutated gene‐encoded protein may serve as a tumor antigen to elicit tumor‐specific immune responses. In this study, we detected widespread expression of shared TP53‐Y220C neoantigen in hepatocellular carcinoma with low affinity and low stability of binding to HLA‐A0201 molecules. We substituted the amino acid sequences VVPCEPPEV with VLPCEPPEV in the TP53‐Y220C neoantigen to yield a TP53‐Y220C (L2) neoantigen. This altered neoantigen was found to increase affinity and stability and induce more cytotoxic T lymphocytes (CTLs), indicating improvements in immunogenicity. In vitro assays showed the cytotoxicity of CTLs stimulated by both TP53‐Y220C and TP53‐Y220C (L2) neoantigens against multiple HLA‐A0201‐positive cancer cells expressing TP53‐Y220C neoantigens; however, the TP53‐Y220C (L2) neoantigen showed higher cytotoxicity than the TP53‐Y220C neoantigen against cancer cells. More importantly, in vivo assays demonstrated greater inhibition of hepatocellular carcinoma cell proliferation by TP53‐Y220C (L2) neoantigen‐specific CTLs relative to TP53‐Y220C neoantigen in zebrafish and nonobese diabetic/severe combined immune deficiency mouse models. The results of this study demonstrate enhanced immunogenicity of the shared TP53‐Y220C (L2) neoantigen, which has the potential as dendritic cells or peptide vaccines for multiple cancers. [ABSTRACT FROM AUTHOR]

Staphylococcus aureus has been widely reported to be majorly responsible for causing nosocomial infections worldwide. Due to an increase in antibiotic‐resistant strains, the development of an effective vaccine against the bacteria is the most viable alternative. Therefore, in the current work, an effort has been undertaken to develop a novel peptide‐based vaccine construct against S aureus that can potentially evoke the B and T cell immune responses. The fibronectin‐binding proteins are an attractive target as they play a prominent role in bacterial adherence and host cell invasion and are also well conserved among rapidly mutating pathogens. Therefore, highly immunogenic linear B lymphocytes (LBL), cytotoxic T lymphocytes (CTL), and helper T lymphocytes (HTL) epitopes were identified from the antigenic fibronectin‐binding proteins A and B (FnBPA and FnBPB) of S aureus using immunoinformatics approaches. The selected peptides were confirmed to be non‐allergenic, non‐toxic, and with a high binding affinity to the majority of human leukocyte antigens (HLA) alleles. Consequently, the multi‐peptide vaccine construct was developed by fusing the screened epitopes (three LBL, five CTL, and two HTL) together with the suitable adjuvant and linkers. In addition, the tertiary conformation of the peptide construct was modeled and later docked to the Toll‐like receptor 2. Subsequently, a molecular dynamics simulation of 100 ns was employed to corroborate the stability of the designed vaccine‐receptor complex. Besides exhibiting high immunogenicity and conformational stability, the developed vaccine was observed to possess wide population coverage of 99.51% worldwide. Additional in vivo and in vitro validation studies would certainly corroborate the designed vaccine construct to have improved prophylactic efficacy against S aureus. Staphylococcus aureus is a major cause of nosocomial infections worldwide, and the development of an effective vaccine against it is the most viable alternative. This work has been undertaken to develop a novel peptide‐based vaccine construct against S. aureus that can evoke the B and T cell immune responses. [ABSTRACT FROM AUTHOR]

Materials‐based antigen delivery systems can augment the immune response by improving antigen uptake in antigen‐presenting cells, targeting lymph nodes, prolonging antigen exposure, enhancing cross‐presentation, etc. Recent research revealed that some antigen carriers activate the innate immune pathways without additional adjuvant. Here, a vaccine delivery platform (antigen nanocapsules) constructed by a one‐step in situ polymerization is reported, weaving a biodegradable polymer network around the antigen surface. This simple technology allowed us to study the immunomodulatory effect of various antigen carriers. An antigen nanocapsule (NC7) capable of inducing dendritic cell activation and cross‐presentation is identified. Further mechanistic studies revealed that NC7 activated the cGAS‐STING pathway in a cGAS‐dependent manner. Moreover, the subcutaneously injected NC7 accumulated in the lymph nodes and elicited strong cytotoxic T cell immunity and T cell memory against established cancer. Collectively, the often‐neglected immunomodulatory effect of various cationic antigen carriers, enabling potential application in cancer vaccines, is uncovered. [ABSTRACT FROM AUTHOR]

There is, at present, only two models of the TCR structure-function relationship. These are referred to here as the Standard (Centric) model and the Tritope model. While I have argued that the Standard model is untenable and proposed the Tritope to replace it, Bretscher has argued that the Tritope model is 'implausible' and throws his support for the Standard model. This essay analyses the implausibility argument concluding that it is unfounded. [ABSTRACT FROM AUTHOR]

The article features allergy/immunology authority Rolf M. Zinkernagel and his co-discovery of MHC molecules' restriction of antiviral cytotoxic T cells with colleague Peter Doherty. It states that the discovery clarified cytotoxic T cells' interaction with their target cells, and the importance of the process in understanding the immune system's development and function. Also noted is the MHC restriction's facilitation of selective stimulation of immune reactions in inflammatory diseases.

Two major chaperones, calreticulin (CRT) and binding immunoglobulin protein (GRP78/BiP) dependent on their location, have immunoregulatory or anti‐inflammatory functions respectively. CRT induces pro‐inflammatory cytokines, dendritic cell (DC) maturation and activates cytotoxic T cells against tumours. By contrast, GRP78/BiP induces anti‐inflammatory cytokines, inhibits DC maturation and heightens T‐regulatory cell responses. These latter functions rebalance immune homeostasis in inflammatory diseases, such as rheumatoid arthritis. Both chaperones are therapeutically relevant agents acting primarily on monocytes/DCs. Endogenous exposure of CRT on cancer cell surfaces acts as an 'eat‐me' signal and facilitates improved elimination of stressed and dying tumour cells by DCs. Therefore, therapeutics that promote endogenous CRT translocation to the cell surface can improve the removal of cancer cells. However, infused recombinant CRT dampens this cancer cell eradication by binding directly to the DCs. Low levels of endogenous BiP appear as a surface biomarker of endoplasmic reticulum (ER) stress in some types of tumour cells, a reflection of cells undergoing proliferation, in which resulting hypoxia and nutrient deprivation perturb ER homeostasis triggering the unfolded protein response, leading to increased expression of GRP78/BiP and altered cellular location. Conversely, infusion of an analogue of GRP78/BiP (IRL201805) can lead to long‐term immune resetting and restoration of immune homeostasis. The therapeutic potential of both chaperones relies on them being relocated from their intracellular ER environment. Ongoing clinical trials are employing therapeutic interventions to either enhance endogenous cell surface CRT or infuse IRL201805, thereby triggering several disease‐relevant immune responses leading to a beneficial clinical outcome. [ABSTRACT FROM AUTHOR]