An Engineered IL15 Cytokine Mutein Fused to an Anti-PD1 Improves Intratumoral T-cell Function and Antitumor Immunity
Yuanming XuLucia Campos CarrascosaYik A. YeungMatthew Ling-Hon ChuWenjing YangIvana M. DjureticDanielle C. PappasJohn ZeytounianZhouhong GeValeska de RuiterGabriel R. Starbeck-MillerJames C. PattersonDiamanda RigasShih-Hsun ChenEugenia KraynovPatrick P.C. BoorLisanne NoordamMichael DoukasDave TsaoJan N.M. IJzermansJie GuoDirk J. GrünhagenJoris I. ErdmannJoanne VerheijMartin E. van RoyenPascal G. DoorneboschR. M. Renny FeldmanTerrence ParkSalah MahmoudiMagdalena DorywalskaIrene NiSherman M. ChinTına MistryLidia MosyakLaura LinKeith A. ChingKevin C. LindquistChanghua JiLuz M. LondonoBing KuangRobert C. RickertJaap KwekkeboomDave SprengersTzu-Hsuan HuangJavier Chaparro‐Riggers
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The use of cytokines for immunotherapy shows clinical efficacy but is frequently accompanied by severe adverse events caused by excessive and systemic immune activation. Here, we set out to address these challenges by engineering a fusion protein of a single, potency-reduced, IL15 mutein and a PD1-specific antibody (anti-PD1-IL15m). This immunocytokine was designed to deliver PD1-mediated, avidity-driven IL2/15 receptor stimulation to PD1+ tumor-infiltrating lymphocytes (TIL) while minimally affecting circulating peripheral natural killer (NK) cells and T cells. Treatment of tumor-bearing mice with a mouse cross-reactive fusion, anti-mPD1-IL15m, demonstrated potent antitumor efficacy without exacerbating body weight loss in B16 and MC38 syngeneic tumor models. Moreover, anti-mPD1-IL15m was more efficacious than an IL15 superagonist, an anti-mPD-1, or the combination thereof in the B16 melanoma model. Mechanistically, anti-PD1-IL15m preferentially targeted CD8+ TILs and single-cell RNA-sequencing analyses revealed that anti-mPD1-IL15m treatment induced the expansion of an exhausted CD8+ TIL cluster with high proliferative capacity and effector-like signatures. Antitumor efficacy of anti-mPD1-IL15m was dependent on CD8+ T cells, as depletion of CD8+ cells resulted in the loss of antitumor activity, whereas depletion of NK cells had little impact on efficacy. The impact of anti-hPD1-IL15m on primary human TILs from patients with cancer was also evaluated. Anti-hPD1-IL15m robustly enhanced the proliferation, activation, and cytotoxicity of CD8+ and CD4+ TILs from human primary cancers in vitro, whereas tumor-derived regulatory T cells were largely unaffected. Taken together, our findings showed that anti-PD1-IL15m exhibits a high translational promise with improved efficacy and safety of IL15 for cancer immunotherapy via targeting PD1+ TILs.See related Spotlight by Felices and Miller, p. 1110.Acquired immunity to Schistosoma mansoni in the rat can be assayed by the recovery of a proportion of the schistosomula of a challenge infection from the lungs 5 days after the challenge has been given. The recoveries from immune rats, which are significantly less than those from control animals, demonstrate that a proportion of a challenge infection is killed in the lungs or at an earlier point in the pathway of migration. Immunity in the Sprague–Dawley rat can first be shown by the lung recovery technique 3 weeks after an immunizing exposure of 500 cercariae. Immunity reaches a peak between weeks 6 and 7 but then declines to zero by week 12. The PVG inbred Hooded rat shows a similar but delayed development and decline of immunity. When the lung recovery technique shows immunity to be declining, hepatic perfusion demonstrates that immunity to reinfection is partially retained, indicating that at this stage the challenge is killed after the first 5 days. Re-exposure of rats in which immunity has declined induces an anamnestic lung recovery response. There appears to be a relationship between spontaneous cure and the decline of immunity. A factor in the serum of infected rats which kills young schistosomula in culture develops in parallel with immunity, but high titres of this factor are maintained during the decline of immunity.
Humoral immunity
Cellular immunity
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The immune system, which has various general functions in the body, is also in close interaction with some physiological processes and body systems. The new coronavirus disease (COVID-19), which is known to have a more severe course in individuals whose immune system does not work rapidly and who has a weak immune response, has created a pandemic effect all over the world. Diet affects the composition of gut microbiota which has important effects on immunity and inflamatory responses. Fermentation of carbohydrates that reach the colon without being digested, short-chain fatty acids are play an important role in metabolism with their anti-inflammatory, anticarcinogenic, immunomodulatory and cell proliferation effects. Considering the role of the immune system in COVID-19, selection of carbonhydrates from complex and high dietary fiber intake may benefit the treatment strategy in these patients by providing immunomodulatory function.
Coronavirus
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This review will provide an overview of cytokine and cytokine-based immunotherapy and focus on recent developments in new-era oncological treatment, including several combinations of both conventional cancer therapy and novel immunotherapy with cytokine, and their applications in clinical research. There are five main parts, (1) The technology of cytokine immunotherapy, (2) The function of cytokine immunotherapy and defects of cytokine as a monotherapy, (3) The specific cancers that are targeted by synergistic cytokine immunotherapy, and (4) Prospects of cytokine in immunotherapy.
Cancer Immunotherapy
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Summary In many vertebrates, immune activity is compromised when other expensive activities are concurrent. One explanation for such patterns includes trade‐offs between immune activity and other expensive physiological processes. Trade‐offs among different immune responses themselves may also occur, but thus far few data exist to substantiate them. We predicted that immune activity in female White‐footed Mice, Peromyscus leucopus , would be weak (relative to sham‐treated controls) if another immune response was already ongoing. To test this hypothesis, we examined (i) the effects of inflicting a cutaneous wound on cell‐mediated immune activity one day after wounding, and (ii) the effects of inducing cell‐mediated immune activity on the cutaneous wound‐healing process when wounds were inflicted one day after the immune challenge. Prior wounding dampened cell‐mediated immune responses and induction of cell‐mediated immune activity altered progression of wound healing. Immune challenges did not affect reproductive tissue masses, however, as has been detected in males of this species. Also, concentrations of circulating glucocorticoids, which are known modulators of immune activity, were not dramatically different between treatment and sham groups. In sum, our results provide evidence that some immune responses can negatively influence other recent immunological activity. Further study is warranted, however, to pinpoint the molecular mechanisms underlying these apparent trade‐offs and determine whether induction of immune activity may sometimes prime instead of hinder subsequent immune responses.
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Immune cells and commensal microbes in the human intestine constantly communicate with and react to each other in a stable environment in order to maintain healthy immune activities. Immune system-microbiota cross-talk relies on a complex network of pathways that sustain the balance between immune tolerance and immunogenicity. Probiotic bacteria can interact and stimulate intestinal immune cells and commensal microflora to modulate specific immune functions and immune homeostasis. Growing evidence shows that probiotic bacteria present important health-promoting and immunomodulatory properties. Thus, the use of probiotics might represent a promising approach for improving immune system activities. So far, few studies have been reported on the beneficial immune modulatory effect of probiotics. However, many others, which are mainly focused on their metabolic/nutritional properties, have been published. Therefore, the mechanisms behind the interaction between host immune cells and probiotics have only been partially described. The present review aims to collect and summarize the most recent scientific results and the resulting implications of how probiotic bacteria and immune cells interact to improve immune functions. Hence, a description of the currently known immunomodulatory mechanisms of probiotic bacteria in improving the host immune system is provided.
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Immune receptor
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Immune cells is the material basis of immune function,an important means to understand the state of the immune function is various immune cells counts and function test.There are a series of unbalance in recurrent genital herpes patients′ immune cell function,including the changes of number of T lymphocytes,NK cells and LAK cells,dendritic cells,and its secreted cell factors,which then lead to the body′s low cells immune response,immune suppression,or immune defect.Through the research of the unbalance change of related immune cells,theory basis for the prevention and treatment direction of the disease will be established.
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To investigate the dynamic variation of AVP mRNA expression in the paraventricular nucleus of hypothalamus during immune responses in rats and further reveal the genetic modulating mechanisms by which nervous system modulates the immune function.The multiple points, locations and ways of bull serum albumin (BSA) injection were used to establish immune-enhancing animal models, and the lower doses and 1 day interval of CY intraperitoneal injection were used to establish immune-suppressing animal models. In the different periods of the immune response, the serum and the brain of the same rat were taken to be tested at the same time.Six days after primary antigen stimulating the levels of IgG and IL-2 began to escalate, and 6 days after the antigen restimulating the IgG and IL-2 reached the highest level. After the first two CY injections the levels of IgG and IL-2 began to decline, and after 4 CY injections the IgG and IL-2 reached the lowest level.BSA and CY are ideal agents for establishing immune-enhancing and immune-suppressing animal models. BSA could enhance both the humorous and cellular immune function directly. The CY could directly suppress the cellular immune function, but it could indirectly suppress the humorous immune function.
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There is no longer a question regarding whether the immune system functions as an independent system that regulates itself. It does not. The function of the immune system is modulated by hormones released from nerves, the pituitary, the adrenals, and possibly even lymphocytes themselves. Many of the immune regulatory hormones change in concentration at times of different emotional states. Thus, the response to a stressor, which increases the concentration of hormones such as glucocorticoids and catecholamines, modulates immune function. This brief review highlights some of the important areas of clinical interest in the interaction between stress and immune function.
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