Cytotoxic Immune Cells Research Articles

The prognostic impact of the immune signature in head and neck squamous cell carcinoma.

Head and neck squamous cell carcinoma (HNSCC) is a heterogeneous group of tumors that retain their poor prognosis despite recent advances in their standard of care. As the involvement of the immune system against HNSCC development is well-recognized, characterization of the immune signature and the complex interplay between HNSCC and the immune system could lead to the identification of novel therapeutic targets that are required now more than ever. In this study, we investigated RNA sequencing data of 530 HNSCC patients from The Cancer Genome Atlas (TCGA) for which the immune composition (CIBERSORT) was defined by the relative fractions of 10 immune-cell types and expression data of 45 immune checkpoint ligands were quantified. This initial investigation was followed by immunohistochemical (IHC) staining for a curated selection of immune cell types and checkpoint ligands markers in tissue samples of 50 advanced stage HNSCC patients. The outcome of both analyses was correlated with clinicopathological parameters and patient overall survival. Our results indicated that HNSCC tumors are in close contact with both cytotoxic and immunosuppressive immune cells. TCGA data showed prognostic relevance of dendritic cells, M2 macrophages and neutrophils, while IHC analysis associated T cells and natural killer cells with better/worse prognostic outcome. HNSCC tumors in our TCGA cohort showed differential RNA over- and underexpression of 28 immune inhibitory and activating checkpoint ligands compared to healthy tissue. Of these, CD73, CD276 and CD155 gene expression were negative prognostic factors, while CD40L, CEACAM1 and Gal-9 expression were associated with significantly better outcomes. Our IHC analyses confirmed the relevance of CD155 and CD276 protein expression, and in addition PD-L1 expression, as independent negative prognostic factors, while HLA-E overexpression was associated with better outcomes. Lastly, the co-presence of both (i) CD155 positive cells with intratumoral NK cells; and (ii) PD-L1 expression with regulatory T cell infiltration may hold prognostic value for these cohorts. Based on our data, we propose that CD155 and CD276 are promising novel targets for HNSCC, possibly in combination with the current standard of care or novel immunotherapies to come.

346 (PB126) - Preventing cystatin F proteolytic activation by cathepsin V increases cytotoxicity of effector immune cells

Background: Granule-dependent cytotoxicity of natural killer cells and cytotoxic T lymphocytes is regulated by the proteolytic network. Cysteine cathepsins C, H and L are needed for the activation of granzymes and perforin, which initiate the killing of target cancer cells. Activity of cathepsins C, H and L is inhibited by cystatin F. Therefore, cystatin F can negatively impact the cytotoxicity of immune cells. Activity of cystatin F is regulated by expression levels, N-glycosylation and proteolytic activation.

Positron Emission Tomography Probes for Imaging Cytotoxic Immune Cells.

Non-invasive positron emission tomography (PET) imaging of immune cells is a powerful approach for monitoring the dynamics of immune cells in response to immunotherapy. Despite the clinical success of many immunotherapeutic agents, their clinical efficacy is limited to a subgroup of patients. Conventional imaging, as well as analysis of tissue biopsies and blood samples do not reflect the complex interaction between tumour and immune cells. Consequently, PET probes are being developed to capture the dynamics of such interactions, which may improve patient stratification and treatment evaluation. The clinical efficacy of cancer immunotherapy relies on both the infiltration and function of cytotoxic immune cells at the tumour site. Thus, various immune biomarkers have been investigated as potential targets for PET imaging of immune response. Herein, we provide an overview of the most recent developments in PET imaging of immune response, including the radiosynthesis approaches employed in their development.

Abstract A025: Profiling tumor infiltrating immune cells for better understanding tumor status and better response to therapeutic strategy in soft tissue sarcomas

Abstract The tumor microenvironment is closely associated with tumor development and progression, which is made up of tumor cells, blood vessels, immune cells, fibroblast, and so on. Especially, immune cells within tumor microenvironments have been attracted in clinicians and researchers for unexpected therapeutic responses. Even in sarcoma, which is rare, and heterogenous leading to few options for cure, immune therapy has been tried and shown to be promising. However, the information of immune cells within soft tissue sarcomas were limited, which mostly have been obtained and characterized by omics-based analyses or tissue staining such as immunohistochemistry. Here, we established platform to profile tumor infiltrating immune cells by flow cytometry. About thirty sarcoma tissues were obtained, in which tumor infiltrating immune cells were profiled. The profiled data were confirmed by immunohistochemistry for correlation. It was shown that infiltrated leukocytes and CD3+ T cells were remarkably increased, whereas NKT and CD4+ T cells were decreased in tumor tissues compared to adjacent normal tissues. M1 macrophage was also increased in tumor tissues. High CD3+ T cell population was positively correlated with CD8+ T cells and PD1+ CD8+ T cell population. Especially, PD1+CD8+ T cells are usually expressed exhaustion-related conditions and low levels of cytotoxic immune cells. This study provides resources to understand immune cell population of soft tissue sarcoma, and will gain a fundamental matrix to study immunotherapy. These studies might show the possibility to find potential prognostic and immunotherapeutic targets. Citation Format: Eun-Young Lee, Hyun Guy Kang, June Hyuk Kim, Jong Woong Park, Seog Yun Park, Tak Yun, Hye Jin You. Profiling tumor infiltrating immune cells for better understanding tumor status and better response to therapeutic strategy in soft tissue sarcomas [abstract]. In: Proceedings of the AACR Special Conference: Sarcomas; 2022 May 9-12; Montreal, QC, Canada. Philadelphia (PA): AACR; Clin Cancer Res 2022;28(18_Suppl):Abstract nr A025.

The effects of acute exercise and inflammation on immune function in early-stage prostate cancer

BackgroundThe immune system plays a vital role in cancer development and progression. Strategies mobilizing cytotoxic cells of the immune system to combat immunosuppression in cancer may help to improve the treatment response of patients. To this end, we aimed to characterize the anti-cancer effect of acute exercise, including the involvement of inflammatory signals. Patients and methodsTwenty patients with early-stage prostate cancer (PCa) scheduled to undergo prostatectomy performed one bout of acute exercise consisting of a watt-max test and four high-intensity intervals. Natural Killer (NK), NKT-like and T cell phenotype, NK cell cytotoxic activity (NKCA), and NKCA per-cell against cell lines of leukemia (K562) and prostate cancer origin (LNCaP and PC-3) were assessed. Inflammatory markers (TNF-α, IL-6, and CRP) were measured in plasma. ResultsExercise increased NK, NKT-like, and CD8 T cell concentration in the circulation. Furthermore, exercise shifted immune cells towards a mature and cytotoxic phenotype e.g., NK cells exhibited higher CD57 as well as lower NKG2A expression. NKT-like and CD8 cells exhibited elevated CD57, TIGIT and Granzyme-B expression. Exercise significantly improved NKCA against K562 (+16% [5%; 27%]; p = 0.002) and LNCaP (+24% [14%; 34%]; p < 0.001) but not PC-3. NKCA per NK cell decreased during exercise and increased 1-h post exercise compared to baseline in K562, LNCap, and PC-3 cell lines. Baseline IL-6 correlated with lymphocyte, monocyte and T cell concentration pre-exercise and inversely correlated with the fold-change of mobilized lymphocytes and CD8 T cells during exercise. Furthermore, baseline IL-6 and TNF-α inversely correlated with NKCA against PC-3 cells during exercise. ConclusionsAcute exercise mobilized cytotoxic immune cells and improved NKCA in patients with PCa whereas low-grade inflammation might impair the response. Whether the observed improvements impact long-term outcomes warrant further investigation. Clinical trial numberNCT03675529.

Nemvaleukin alfa, a novel engineered IL-2 fusion protein, drives antitumor immunity and inhibits tumor growth in small cell lung cancer

BackgroundSmall cell lung cancer (SCLC) is a deadly disease with a 5-year survival of less than 7%. The addition of immunotherapy to chemotherapy was recently approved as first-line treatment; however,...

Monitoring Cellular Immune Responses after Consumption of Selected Probiotics in Immunocompromised Mice.

Probiotics are currently considered as one of tools to modulate immune responses under specific clinical conditions. The purpose of this study was to evaluate whether oral administration of three different probiotics (Lactiplantibacillus plantarum CJLP243, CJW55-10, and CJLP475) could evoke a cell-mediated immunity in immunodeficient mice. Before conducting in vivo experiments, we examined the in vitro potency of these probiotics for macrophage activation. After co-culture with these probiotics, bone marrow derived macrophages (BMDMs) produced significant amounts of proinflammatory cytokines including interleukin-6 (IL-6), IL-12, and tumor necrosis factor-α (TNF-α). Levels of inducible nitric oxide synthase (inos) and co-stimulatory molecules (CD80 and CD86) were also upregulated in BMDMs after treatment with some of these probiotics. To establish an immunocompromised animal model, we intraperitoneally injected mice with cyclophosphamide on day 0 and again on day 2. Starting day 3, we orally administered probiotics every day for the last 15 d. After sacrificing experimental mice on day 18, splenocytes were isolated and co-cultured with these probiotics for 3 d to measure levels of several cytokines and immune cell proliferation. Results clearly indicated that the consumption of all three probiotic strains promoted secretion of interferon-γ (IFN-γ), IL-1β, IL-6, IL-12, and TNF-α. NK cell cytotoxicity and proliferation of immune cells were also increased. Taken together, our data strongly suggest that consumption of some probiotics might induce cell-mediated immune responses in immunocompromised mice.

Abstract P073: Long-term Augmentation Of Acetylcholine Bioavailability Halts The Progression Of Lupus Hypertension

Renal inflammation promotes hypertension in systemic lupus erythematosus (SLE). Our recent studies suggest that renal inflammation is regulated by the vagally-mediated cholinergic anti-inflammatory pathway, and that vagal tone is reduced in SLE mice. We found that augmenting central bioavailability of acetylcholine via the acetylcholinesterase inhibitor, galantamine, increases vagal tone and reduces renal inflammation and mean arterial pressure (MAP) in SLE mice after two weeks. However, the long-term efficacy and therapeutic potential of galantamine are unknown. Thus, we hypothesized that chronic galantamine administration would effectively halt the progression of SLE hypertension and renal injury. Starting at 20 weeks of age, female SLE ( NZBWF1 ) and control ( NZW ) mice received galantamine hydrobromide (3 mg/kg/day, SQ) or vehicle continuously for 16 weeks via osmotic minipump. At 35 weeks, mice were placed in metabolic cages for urine collection, carotid catheters were implanted to assess MAP in conscious mice, and tissues were harvested. MAP (mmHg, n=4-6) was higher in SLE mice than controls (161.9±9.9 vs. 128.3±0.9, p=0.001) and long-term galantamine treatment prevented further increases in MAP in SLE mice (161.9±9.9 vs. 138.3±4.9, p= 0.01). Survival rate was lower in SLE mice compared to controls (50% vs. 100%) and galantamine improved survival to 70% in SLE mice. Eighty percent (4 of 5) of SLE mice had urinary albumin over 300 mg/dL and chronic galantamine lowered the prevalence to 57% (4 of 7); no controls had albuminuria. There was no difference in CD3+CD4+ T cells amongst groups, but the percentage of renal CD3+CD8+ T cells was increased in SLE mice compared to controls (29.7±2.2 vs. 12.8±0.79, p&lt;0.0001, n=4-7) and galantamine reduced this percentage in SLE mice (29.7±2.2 vs. 22.9±1.2, p=0.0261). Taken together, our data indicate chronic augmentation of central acetylcholine bioavailability is protective against SLE hypertension since it improves survival rate, decreases renal injury and alters cytotoxic renal immune cell populations. These data further support acetylcholinesterase inhibition as a novel therapeutic option for hypertension associated with autoimmunity.

Bispecific antibody-derived molecules to target persistent HIV infection

HIV infection persists despite durable and potent antiviral therapy. To target persistent HIV infection, one major strategy aims to induce HIV provirus expression using latency reversing agents and then eliminate these reservoir cells via immune responses enhanced by treatment with antibody-derived bispecific molecules. The specificities of anti-HIV-1 envelope monoclonal antibodies have been incorporated into bispecific molecules that can recognize infected cells and recruit cytotoxic immune cells to eliminate them. This concept seeks to engineer a unique and potent effector response based on the opportunity to target conserved viral epitopes on infected cells, and recruit broad populations of immune effector cells that are not limited by major histocompatibility complex restrictions or other programmed specificity constraints. This article provides a review of bispecific DART® molecules and other dual-specificity antibody-based molecules that function by co-engaging CD3-expressing T cells or CD16A-expressing NK cells with HIV-1-infected cells.

Metal-Cyclic Dinucleotide Nanomodulator-Stimulated STING Signaling for Strengthened Radioimmunotherapy of Large Tumor.

Combined treatment of immunotherapy and radiotherapy shows promising therapeutic effects for the regression of a variety of cancers. However, even multi-modality therapies often fail to antagonize the regression of large tumors due to the extremely immunosuppressive tumor microenvironment (TME). Here, a radioimmunotherapeutic paradigm based on stimulator of interferon genes (STING)-dependent signaling is applied to preclude large tumor progression by utilizing the metal-cyclic dinucleotide (CDN) nanoplatform, which integrates STING agonist c-di-AMP and immunomodulating microelement manganese (II) within the tannic acid nanostructure (TMA-NPs). As observed by magnetic resonance imaging, the localized administration of TMA-NPs effectively relieves hypoxia within TME and causes radical oxygen species overproduction and apoptosis in cancer cells after exposure to X-ray irradiation. The DNA fragments released from the apoptotic cells after the combined treatment augment the production of endogenous CDNs in cancer cells, hence significantly activating the STING-mediated pathway for stronger anti-tumor immunity. The localized therapy of TMA-NPs + X-ray not only inhibits the primary large tumor progression but also retards distant tumor growth by promoting dendritic cell maturation and activating cytotoxic immune cells whil suppressing immunosuppressive cells. Therefore, this work represents the combinatorial potency of TMA-NPs and X-rays on large tumor regression through strengthened STING-mediated radioimmunotherapeutics.

Live Biotherapeutic Lactococcus lactis GEN3013 Enhances Antitumor Efficacy of Cancer Treatment via Modulation of Cancer Progression and Immune System.

Simple SummaryRecent studies, which have revealed the strong relationship between gut microbiota and tumor progression, have driven the clinical application of microbiome-based treatments to increase the efficacy of anticancer therapies. In particular, the genome-editing Lactococcus lactis, which activates the host immune system by expressing immune-boosting cytokines or metabolites, is a candidate for microbiome treatment. While Lactococcus lactis has so far been studied in terms of its recombinant forms, we investigated the anticancer effects of the strain-specific Lactococcus lactis GEN3013 itself. In vitro cytotoxicity tests showed that L. lactis GEN3013 inhibited the cell growth of various human and murine cancer cell lines. Consistent with the in vitro results, L. lactis GEN3013 showed antitumor effects and enhanced the therapeutic efficacy of both chemotherapy and immunotherapy in syngeneic mice. In addition, the host immune system was activated both locally and systemically by the combinatorial treatment of L. lactis GEN3013 with chemotherapy and immunotherapy. For these reasons, we suggest that L. lactis GEN3013 could be utilized as a novel biotherapeutic agent for cancer treatment.The gut microbiota is responsible for differential anticancer drug efficacies by modulating the host immune system and the tumor microenvironment. Interestingly, this differential effect is highly strain-specific. For example, certain strains can directly suppress tumor growth and enhance antitumor immunity; however, others do not have such an effect or even promote tumor growth. Identifying effective strains that possess antitumor effects is key for developing live biotherapeutic anticancer products. Here, we found that Lactococcus lactis GEN3013 inhibits tumor growth by regulating tumor angiogenesis and directly inducing cancer cell death. Moreover, L. lactis GEN3013 enhanced the therapeutic effects of oxaliplatin and the PD-1 blockade. Comprehensive immune profiling showed that L. lactis GEN3013 augmented cytotoxic immune cell populations, such as CD4+ T cells, CD8+ effector T cells, and NK cells in the tumor microenvironment. Our results indicate that L. lactis GEN3013 is a promising candidate for potentiating cancer treatment in combination with current standard therapy.

ACO1 and IREB2 downregulation confer poor prognosis and correlate with autophagy-related ferroptosis and immune infiltration in KIRC.

BackgroundACO1 and IREB2 are two homologous cytosolic regulatory proteins, which sense iron levels and change iron metabolism–linked molecules. These two genes were noticeably decreased in kidney renal clear cell carcinoma (KIRC), which confer poor survival. Meanwhile, there is a paucity of information about the mechanisms and clinical significance of ACO1 and IREB2 downregulation in renal cancers.MethodsThe expression profiles of ACO1 and IREB2 were assessed using multiple public data sets via several bioinformatics platforms. Clinical and pathological information was utilized to stratify cohorts for comparison. Patient survival outcomes were evaluated using the Kaplan–Meier plotter, a meta-analysis tool. The correlations of ACO1 and IREB2 with ferroptosis were further evaluated in The Cancer Genome Atlas (TCGA)–KIRC database. Tumor immune infiltration was analyzed using the CIBERSORT, TIMER, and GEPIA data resources. ACO1 antagonist sodium oxalomalate (OMA) and IREB2 inhibitor sodium nitroprusside (SNP) was used to treat renal cancer ACHN cells together with sorafenib.ResultsKIRC patients with low ACO1 or IREB2 contents exhibited a remarkably worse survival rate in contrast with those with high expression in Kaplan–Meier survival analyses. Meanwhile, ACO1 and IREB2 regulate autophagy-linked ferroptosis along with immune cell invasion in the tumor microenvironment in KIRC patients. Blocking the activation of these two genes by their inhibitors OMA and SNP ameliorated sorafenib-triggered cell death, supporting that ACO1 and IREB2 could be participated in its cytotoxic influence on renal cancer cells.ConclusionACO1 and IREB2 downregulation in renal cancers were correlated with cancer aggressiveness, cellular iron homeostasis, cytotoxic immune cell infiltration, and patient survival outcomes. Our research is integral to verify the possible significance of ACO1 and IREB2 contents as a powerful signature for targeted treatment or novel immunotherapy in clinical settings.

In Vitro Assay of Plasmodium-Infected Red Blood Cell Killing by Cytotoxic Lymphocytes.

Malaria is a major public health concern, presenting more than 200 million cases per year worldwide. Despite years of scientific efforts, protective immunity to malaria is still poorly understood, mainly due to methodological limitations of long-term Plasmodium culture, especially for Plasmodium vivax. Most studies have focused on adaptive immunity protection against malaria by antibodies, which play a key role in controlling malaria. However, the sterile protection induced by attenuated Plasmodium sporozoites vaccines is related to cellular response, mainly to cytotoxic T lymphocytes, such as CD8+ and gamma delta T cells (γδ T). Hence, new methodologies must be developed to better comprehend the functions of the cellular immune response and thus support future therapy and vaccine development. To find a new strategy to analyze this cell-mediated immunity to Plasmodium blood-stage infection, our group established an in vitro assay that measures infected red blood cell (iRBC) killing by cytotoxic lymphocytes. This assay can be used to study cellular immune response mechanisms against different Plasmodium spp. in the blood stage. Innate and adaptative cytotoxic immune cells can directly eliminate iRBCs and the intracellular parasite in an effector:target mechanism. Target iRBCs are labeled to evaluate cell viability, and cocultured with effector cells (CD8+ T, γδ T, NK cells, etc.). The lysis percentage is calculated based on tested conditions, compared to a spontaneous lysis control in a flow cytometry-based assay. Ultimately, this killing assay methodology is a major advance in understanding cell-mediated immunity to blood-stage malaria, helping uncover new potential therapeutic targets and accelerate the development of malaria vaccines.

Obesity reduced survival with 5-fluorouracil and did not protect against chemotherapy-induced cachexia or immune cell cytotoxicity in mice

ABSTRACT Fluorouracil/5-flourouracil (5FU) is a first-line chemotherapy drug for many cancer types; however, its associated toxicities contribute to poor quality of life and reduced dose intensities negatively impacting patient prognosis. While obesity remains a critical risk factor for most cancers, our understanding regarding how obesity may impact chemotherapy’s toxicities is extremely limited. C56BL/6 mice were given high fat (Obese) or standard diets (Lean) for 4 months and then subjected to three cycles of 5FU (5d-40 mg/kg Lean Mass, 9d rest) or PBS vehicle control. Shockingly, only 60% of Obese survived 3 cycles compared to 100% of Lean, and Obese lost significantly more body weight. Dihydropyrimidine dehydrogenase (DPD), the enzyme responsible for 5FU catabolism, was reduced in obese livers. Total white blood cells, neutrophils, and lymphocytes were reduced in Obese 5FU compared to Lean 5FU and PBS controls. While adipocyte size was not affected by 5FU in Obese, skeletal muscle mass and myofibrillar cross section area were decreased following 5FU in Lean and Obese. Although adipose tissue inflammatory gene expression was not impacted by 5FU, distinct perturbations to skeletal muscle inflammatory gene expression and immune cell populations (CD45+ Immune cells, CD45+CD11b+CD68+ macrophages and CD45+CD11b+Ly6clo/int macrophage/monocytes) were observed in Obese only. Our evidence suggests that obesity induced liver pathologies and reduced DPD exacerbated 5FU toxicities. While obesity has been suggested to protect against cancer/chemotherapy-induced cachexia and other toxicities, our results demonstrate that obese mice are not protected, but rather show evidence of increased susceptibility to 5FU-induced cytotoxicity even when dosed for relative lean mass.

Interleukin-18 cytokine in immunity, inflammation, and autoimmunity: Biological role in induction, regulation, and treatment.

Interleukin-18 (IL-18) is a potent pro-inflammatory cytokine involved in host defense against infections and regulates the innate and acquired immune response. IL-18 is produced by both hematopoietic and non-hematopoietic cells, including monocytes, macrophages, keratinocytes and mesenchymal cell. IL-18 could potentially induce inflammatory and cytotoxic immune cell activities leading to autoimmunity. Its elevated levels have been reported in the blood of patients with some immune-related diseases, including rheumatoid arthritis, systemic lupus erythematosus, type I diabetes mellitus, atopic dermatitis, psoriasis, and inflammatory bowel disease. In the present review, we aimed to summarize the biological properties of IL-18 and its pathological role in different autoimmune diseases. We also reported some monoclonal antibodies and drugs targeting IL-18. Most of these monoclonal antibodies and drugs have only produced partial effectiveness or complete ineffectiveness in vitro, in vivo and human studies. The ineffectiveness of these drugs targeting IL-18 may be largely due to the loophole caused by the involvement of other cytokines and proteins in the signaling pathway of many inflammatory diseases besides the involvement of IL-18. Combination drug therapies, that focus on IL-18 inhibition, in addition to other cytokines, are highly recommended to be considered as an important area of research that needs to be explored.

Identification of m6A- and ferroptosis-related lncRNA signature for predicting immune efficacy in hepatocellular carcinoma.

BackgroundN6-methyladenosine (m6A) methylation and ferroptosis assist long noncoding RNAs (lncRNAs) in promoting immune escape in hepatocellular carcinoma (HCC). However, the predictive value of m6A- and ferroptosis-related lncRNAs (mfrlncRNAs) in terms of immune efficacy remains unknown.MethodA total of 365 HCC patients with complete data from The Cancer Genome Atlas (TCGA) database were used as the training cohort, and half of them were randomly selected as the validation cohort. A total of 161 HCC patients from the International Cancer Genome Consortium (ICGC) database were used as external validation (ICGC cohort).ResultsWe first identified a group of specific lncRNAs associated with both m6A regulators and ferroptosis-related genes and then constructed prognosis-related mfrlncRNA pairs. Based on this, the mfrlncRNA signature was constructed using the least absolute shrinkage and selection operator (LASSO) analysis and Cox regression. Notably, the risk score of patients was proven to be an independent prognostic factor and was better than the TNM stage and tumor grade. Moreover, patients with high-risk scores had lower survival rates, higher infiltration of immunosuppressive cells (macrophages and Tregs), lower infiltration of cytotoxic immune cells (natural killer cells), poorer immune efficacy (both immunophenoscore and score of tumor immune dysfunction and exclusion), higher IC50, and enrichment of the induced Treg pathway, which confirmed that the mfrlncRNA signature contributed to survival prediction and risk stratification of patients with HCC.ConclusionsThe mfrlncRNA signature, which has great prognostic value, provides new clues for identifying “cold” and “hot” tumors and might have crucial implications for individualized therapy to improve the survival rate of patients with HCC.

Application of lipid-based nanoparticles in cancer immunotherapy.

Immunotherapy is revolutionizing the clinical management of patients with different cancer types by sensitizing autologous or allogenic immune cells to the tumor microenvironment which eventually leads to tumor cell lysis without rapidly killing normal cells. Although immunotherapy has been widely demonstrated to be superior to chemotherapies, only a few populations of patients with specific cancer types respond to such treatment due to the failure of systemic immune activation. In addition, severe immune-related adverse events are rapidly observed when patients with very few responses are given higher doses of such therapies. Recent advances of lipid-based nanoparticles (NPs) development have made it possible to deliver not only small molecules but also mRNAs to achieve systemic anticancer immunity through cytotoxic immune cell activation, checkpoint blockade, and chimeric antigen receptor cell therapies, etc. This review summarized recent development and applications of LNPs in anticancer immunotherapy. The diversity of lipid-based NPs would encapsulate payloads with different structures and molecular weights to achieve optimal antitumor immunity through multiple mechanisms of action. The discussion about the components of lipid-based NPs and their immunologic payloads in this review hopefully shed more light on the future direction of anticancer immunotherapy.

Levamisole Suppresses CD4+ T-Cell Proliferation and Antigen-Presenting Cell Activation in Aplastic Anemia by Regulating the JAK/STAT and TLR Signaling Pathways.

Aplastic anemia (AA) is a life-threatening disease primarily caused by a metabolic disorder and an altered immune response in the bone marrow (BM) microenvironment, where cytotoxic immune cells attack resident cells and lead to hematopoietic failure. We previously reported an efficient strategy by applying cyclosporin (CSA) combined with levamisole (CSA+LMS-based regimen) in the treatment of AA, but the immunoregulatory mechanism of LMS was still unclear. Here, the therapeutic effects of LMS were examined in vivo using the BM failure murine model. Meanwhile, the proportion and related function of T cells were measured by flow cytometry in vivo and in vitro. The involved signaling pathways were screened by RNA-seq and virtual binding analysis, which were further verified by interference experiments using the specific antagonists on the targeting cells by RT-PCR in vitro. In this study, the CSA+LMS-based regimen showed a superior immune-suppressive response and higher recession rate than standard CSA therapy in the clinical retrospective study. LMS improved pancytopenia and extended the survival in an immune-mediated BM failure murine model by suppressing effector T cells and promoting regulatory T-cell expansion, which were also confirmed by in vitro experiments. By screening of binding targets, we found that JAK1/2 and TLR7 showed the highest docking score as LMS targeting molecules. In terms of the underlying molecular mechanisms, LMS could inhibit JAK/STAT and TLR7 signaling activity and downstream involved molecules. In summary, LMS treatment could inhibit T-cell activation and downregulate related molecules by the JAK/STAT and TLR signaling pathways, supporting the valuable clinical utility of LMS in the treatment of AA.

TransCon IL-2 β/γ: a novel long-acting prodrug with sustained release of an IL-2Rβ/γ-selective IL-2 variant with improved pharmacokinetics and potent activation of cytotoxic immune cells for the treatment of cancer

BackgroundRecombinant interleukin-2 (IL-2, aldesleukin) is an approved cancer immunotherapy but causes severe toxicities including cytokine storm and vascular leak syndrome (VLS). IL-2 promotes antitumor function of IL-2Rβ/γ+ natural killer (NK)...

The role of zinc in the pathogenesis and treatment of COVID-19: A review

Destructive outcomes of coronavirus pandemic call for medical research which can report all of the influential agents not only for the treatment of the disease but also preventing its severe impacts on the societal health in the most efficient manner. Zinc plays an integral role in the function of cellular enzymes and transcription factors. Owing to its anti-inflammatory and cellular immunity regulation activity, zinc is regarded to be effective on strengthening the immune system. Its crucial antiviral effects have long been established as well. Studies suggest that low serum zinc level predisposes the patient to severe COVID-19 infection, which makes patient’s zinc profile a potential determinant of prognosis and severity of this disease. Furthermore, zinc supplementation has indicated promising outcomes of coronavirus infection management. Zinc modulates cell-mediated immunity and participates in the killing of microorganisms in cytotoxic immune cells. Zn2+ has anti-inflammatory effects by inhibiting IL-6 production. Although there is still not enough evidence, it seems that zinc could be a promising supplementary treatment for COVID-19 especially in zinc-deficient patients. The aim of this review is to clarify the role of zinc in pathogenesis and therapy of COVID-19 in detail.