Search

Innovations in cancer immunotherapy have resulted in the development of several novel immunotherapeutic strategies that can disrupt immunosuppression. One key advancement lies in immune checkpoint inhibitors (ICIs), which have shown significant clinical efficacy and increased survival rates in patients with various therapy-resistant cancers. This immune intervention consists of monoclonal antibodies directed against inhibitory receptors (e.g., PD-1) on cytotoxic CD8 T cells or against corresponding ligands (e.g., PD-L1/PD-L2) overexpressed on cancer cells and other cells in the tumor microenvironment (TME). However, not all cancer cells respond—there are still poor clinical responses, immune-related adverse effects, adaptive resistance, and vulnerability to ICIs in a subset of patients with cancer. This challenge showcases the heterogeneity of cancer, emphasizing the existence of additional immunoregulatory mechanisms in many patients. Therefore, it is essential to investigate PD-L1's interaction with other oncogenic genes and pathways to further advance targeted therapies and address resistance mechanisms. Accordingly, our aim was to investigate the mechanisms governing PD-L1 expression in tumor cells, given its correlation with immune evasion, to uncover novel mechanisms for decreasing PD-L1 expression and restoring anti-tumor immune responses. Numerous studies have demonstrated that the upregulation of Raf Kinase Inhibitor Protein (RKIP) in many cancers contributes to the suppression of key hyperactive pathways observed in malignant cells, alongside its broadening involvement in immune responses and the modulation of the TME. We, therefore, hypothesized that the role of PD-L1 in cancer immune surveillance may be inversely correlated with the low expression level of the tumor suppressor Raf Kinase Inhibitor Protein (RKIP) expression in cancer cells. This hypothesis was investigated and we found several signaling cross-talk pathways between the regulations of both RKIP and PD-L1 expressions. These pathways and regulatory factors include the MAPK and JAK/STAT pathways, GSK3β, cytokines IFN-γ and IL-1β, Sox2, and transcription factors YY1 and NFκB. The pathways that upregulated PD-L1 were inhibitory for RKIP expression and vice versa. Bioinformatic analyses in various human cancers demonstrated the inverse relationship between PD-L1 and RKIP expressions and their prognostic roles. Therefore, we suspect that the direct upregulation of RKIP and/or the use of targeted RKIP inducers in combination with ICIs could result in a more targeted anti-tumor immune response—addressing the therapeutic challenges related to PD-1/PD-L1 monotherapy alone. [ABSTRACT FROM AUTHOR]

γδ T cells and natural killer (NK) cells have attracted much attention as promising effector cell subsets for adoptive transfer for use in the treatment of malignant and infectious diseases, because they exhibit potent cytotoxic activity against a variety of malignant tumors, as well as virus-infected cells, in a major histocompatibility complex (MHC)-unrestricted manner. In addition, γδ T cells and NK cells express a high level of CD16, a receptor required for antibody-dependent cellular cytotoxicity. Adult T-cell leukemia–lymphoma (ATL) is caused by human T-lymphotropic virus type I (HTLV-1) and is characterized by the proliferation of malignant peripheral CD4+ T cells. Although several treatments, such as chemotherapy, monoclonal antibodies, and allogeneic hematopoietic stem cell transplantation, are currently available, their efficacy is limited. In order to develop alternative therapeutic modalities, we considered the possibility of infusion therapy harnessing γδ T cells and NK cells expanded using a novel nitrogen-containing bisphosphonate prodrug (PTA) and interleukin (IL)-2/IL-18, and we examined the efficacy of the cell-based therapy for ATL in vitro. Peripheral blood samples were collected from 55 patients with ATL and peripheral blood mononuclear cells (PBMCs) were stimulated with PTA and IL-2/IL-18 for 11 days to expand γδ T cells and NK cells. To expand NK cells alone, CD3+ T-cell-depleted PBMCs were cultured with IL-2/IL-18 for 10 days. Subsequently, the expanded cells were examined for cytotoxicity against ATL cell lines in vitro. The proportion of γδ T cells in PBMCs was markedly low in elderly ATL patients. The median expansion rate of the γδ T cells was 1998-fold, and it was 12-fold for the NK cells, indicating that γδ T cells derived from ATL patients were efficiently expanded ex vivo, irrespective of aging and HTLV-1 infection status. Anti-CCR4 antibodies enhanced the cytotoxic activity of the γδ T cells and NK cells against HTLV-1-infected CCR4-expressing CD4+ T cells in an antibody concentration-dependent manner. Taken together, the adoptive transfer of γδ T cells and NK cells expanded with PTA/IL-2/IL-18 is a promising alternative therapy for ATL. [ABSTRACT FROM AUTHOR]

Chronic lymphocytic leukaemia (CLL) is the most common leukaemia among adults. It is the clonal expansion of B cells expressing CD19 and CD5. Despite significant progress in treatment, CLL is still incurable. γδ T cells comprise an important subset of the cytotoxic T cells. Although γδ T cells in CLL are dysfunctional, they still can possibly be used for immunotherapy. The current paper reviews our understanding of γδ T lymphocytes in CLL. [ABSTRACT FROM AUTHOR]

Natural killer T (NKT) cells are unconventional T cells that are activated by glycolipid antigens. They can produce a variety of inflammatory and regulatory cytokines and, therefore, modulate multiple aspects of the immune response in different pathological settings, including autoimmunity. NKT cells have also been implicated in the immunopathogenesis of autoimmune hepatitis, and in this review we summarize and analyze the main studies investigating the involvement and/or homeostasis of NKT cells in this disease. In detail, the evidence from both basic and clinical research has been specifically analyzed. Even though the experimental murine models supported a relevant role of NKT cells in immune-mediated hepatic injury, very few studies specifically investigated NKT cell homeostasis in patients with autoimmune hepatitis; however, these initial studies reported some alterations of NKT cells in these patients, which may also correlate with the disease activity to some extent. Further clinical studies are needed to investigate the potential role and use of NKT cell analysis as a disease marker of clinical relevance, and to better understand the precise cellular and molecular mechanisms by which NKT cells contribute to the pathogenesis of autoimmune hepatitis. [ABSTRACT FROM AUTHOR]

Background: Immune interactions play important roles in the regulation of T cells' cytotoxic function, further impacting the anti-tumor efficacy of immunotherapy. A comprehensive analysis of immune cell types in HCC and immune-cell-related signatures predicting prognosis and monitoring immunotherapy efficacy is still absent. Methods: More than 1,300 hepatocellular carcinomas (HCC) patients were collected from public databases and included in the present study. The ssGSEA algorithm was applied to calculate the infiltration level of 28 immunocyte subpopulations. A cell pair algorithm was applied to construct an immune-cell-related prognostic index (ICRPI). Survival analyses were performed to measure the survival difference across ICRPI risk groups. Spearman's correlation analyses were used for the relevance assessment. A Wilcoxon test was used to measure the expression level's differences. Results: In this study, 28 immune subpopulations were retrieved, and 374 immune cell pairs (ICPs) were established, 38 of which were picked out by the least absolute shrinkage and selection operator (LASSO) algorithm. By using the selected ICPs, the ICRPI was constructed and validated to play crucial roles in survival stratification and dynamic monitoring of immunotherapy effect. We also explored several candidate drugs targeting ICRPI. A composite ICRPI and clinical prognostic index (ICPI) was then constructed, which achieved a more accurate estimation of HCC's survival and is a better choice for prognosis predictions in HCC. Conclusions: In conclusion, we constructed and validated ICRPI based on the cell pair algorithm in this study, which might provide some novel insights for increasing the survival estimation and clinical response to immune therapy for individual HCC patients and contribute to the personalized precision immunotherapy strategy of HCC. [ABSTRACT FROM AUTHOR]

Chronic inflammation of skeletal muscle is the common feature of idiopathic inflammatory myopathies (IIM). Given the rarity of the disease and potential difficulty of routinely obtaining target tissue, i.e., standardized skeletal muscle, our understanding of immune signatures of the IIM spectrum remains incomplete. Further insight into the immune topography of IIM is needed to determine specific treatment targets according to clinical and immunological phenotypes. Thus, we used high-dimensional flow cytometry to investigate the immune phenotypes of anti-synthetase syndrome (ASyS), dermatomyositis (DM) and inclusion-body myositis (IBM) patients as representative entities of the IIM spectrum and compared them to healthy controls. We studied the CD8, CD4 and B cell compartments in the blood aiming to provide a contemporary overview of the immune topography of the IIM spectrum. ASyS was characterized by altered CD4 composition and expanded T follicular helper cells supporting B cell-mediated autoimmunity. For DM, unsupervised clustering identified expansion of distinct B cell subtypes highly expressing immunoglobulin G4 (IgG4) and CD38. Lastly, terminally differentiated, cytotoxic CD8 T cells distinguish IBM from other IIM. Interestingly, these terminally differentiated CD8 T cells highly expressed the integrin CD18 mediating cellular adhesion and infiltration. The distinct immune cell topography of IIM might provide the framework for targeted treatment approaches potentially improving therapeutic outcomes. [ABSTRACT FROM AUTHOR]

In "Cellular Immunology and COVID-19" (a Special Issue of I Cells i ), a panel of leading scientists provides an exhaustive overview of the different aspects of the immune mechanisms underlying COVID-19. Although immunized patients with primary antibody deficiency generated atypical memory B cells, possibly by extra-follicular or incomplete germinal center reactions, SARS-CoV-2 convalescents responded to the infection by generating spike-specific memory B cells that were improved by the subsequent immunization. Moreover, the cytokine hyper activation in COVID-19 appears to be similar to that seen in rheumatoid arthritis, shedding light on the pathological crosstalk between COVID-19 and rheumatoid arthritis, and the aspects of SARS-CoV-2 infection in RA development [[7]]. A dominant spike-derived CD8+ T cell epitope activates a poly functional CD8+ T cell response in recovered COVID-19 patients, possibly being a promising target to prime and boost CD8+ T cells against SARS-CoV-2 infection [[10]]. [Extracted from the article]

Our understanding of the relationship between the immune system and cancers has undergone significant discovery recently. Immunotherapy with T cell therapies and checkpoint blockade has meaningfully changed the oncology landscape. While remarkable clinical advances in adaptive immunity are occurring, modulation of innate immunity has proven more difficult. The myeloid compartment, including macrophages, neutrophils, and dendritic cells, has a significant impact on the persistence or elimination of tumors. Myeloid cells, specifically in the tumor microenvironment, have direct contact with tumor tissue and coordinate with tumor-reactive T cells to either stimulate or antagonize cancer immunity. However, the myeloid compartment comprises a broad array of cells in various stages of development. In addition, hematopoietic stem and progenitor cells at various stages of myelopoiesis in distant sites undergo significant modulation by tumors. Understanding how tumors exert their influence on myeloid progenitors is critical to making clinically meaningful improvements in these pathways. Therefore, this review will cover recent developments in our understanding of how solid tumors modulate myelopoiesis to promote the formation of pro-tumor immature myeloid cells. Then, it will cover some of the potential avenues for capitalizing on these mechanisms to generate antitumor immunity. [ABSTRACT FROM AUTHOR]

Polyamines are ubiquitous, amine-rich molecules with diverse processes in biology. Recent work has highlighted that polyamines exert profound roles on the mammalian immune system, particularly inflammation and cancer. The mechanisms by which they control immunity are still being described. In the context of inflammation and autoimmunity, polyamine levels inversely correlate to autoimmune phenotypes, with lower polyamine levels associated with higher inflammatory responses. Conversely, in the context of cancer, polyamines and polyamine biosynthetic genes positively correlate with the severity of malignancy. Blockade of polyamine metabolism in cancer results in reduced tumor growth, and the effects appear to be mediated by an increase in T-cell infiltration and a pro-inflammatory phenotype of macrophages. These studies suggest that polyamine depletion leads to inflammation and that polyamine enrichment potentiates myeloid cell immune suppression. Indeed, combinatorial treatment with polyamine blockade and immunotherapy has shown efficacy in pre-clinical models of cancer. Considering the efficacy of immunotherapies is linked to autoimmune sequelae in humans, termed immune-adverse related events (iAREs), this suggests that polyamine levels may govern the inflammatory response to immunotherapies. This review proposes that polyamine metabolism acts to balance autoimmune inflammation and anti-tumor immunity and that polyamine levels can be used to monitor immune responses and responsiveness to immunotherapy. [ABSTRACT FROM AUTHOR]

A different approach for T cell-based immunotherapy is illustrated in the commentary by Hafezi et al., where adoptive cell therapy with autologous engineered T cells is considered in case of HBV-related HCC recurrence following liver transplantation. As these patients undergo immunosuppressive treatments that can compromise T cell reactivity, a new class of HBV-specific TCR-redirected T cells can be made temporarily resistant to immunosuppression, thanks to mutations in drug-specific target proteins, thus opening up new ways not only in case of HCC liver transplantation, but also for patients with other pathologies that need immunosuppressant therapies [[9]]. In chronic viral hepatitis and in hepatocarcinoma (HCC), antigen-specific T cells are deeply exhausted, and evidence of dysfunction has also been observed for NK cells, which can play a pathogenetic role, exerting a regulatory activity on adaptive immune responses. [Extracted from the article]

Ewing's sarcoma (EwS) is a pediatric solid tumor entity with low somatic mutational burden and a low rate of tumor-infiltrating T cells, indicating a low extent of immunogenicity. In EwS, immunogenicity may furthermore be significantly diminished by a predominantly M2 macrophage driven pro-tumorigenic tumor microenvironment. In the past, we demonstrated that CHM1319-specific TCR-transgenic T cells are able to control EwS growth in a preclinical mouse model as well as in a patient with metastatic disease. However, new adjuvant techniques to induce long lasting and curative CHM1319-specific TCR-transgenic T cell-mediated anti-tumor responses are needed. In this work, we sought to identify a technique to improve the cytotoxic effect of CHM1319-specific TCR-transgenic T cell by altering the immunogenic cell surface marker expression on EwS cell lines using different cytokines. We demonstrate that TNF, IL-6, IL-1β and PGE2 cause pro-immunogenic CD83, MHC class I and II as well as ICAM-1 upregulation in EwS cell lines. This observation was associated with significantly improved recognition and killing of the tumor cells by EwS-specific CHM1319/HLA-A*02:01-restricted TCR-transgenic T cells. Conclusively, we demonstrate that the induction of an inflammatory signature renders EwS more susceptible to adoptive T cell therapy. TNF, which is upregulated during inflammatory processes, is of particular translational interest as its secretion may be induced in the patients e.g., by irradiation and hyperthermia in the clinical setting. In future clinical protocols, this finding may be important to identify appropriate conditioning regimens as well as point of time for adoptive T cell-based immunotherapy in EwS patients. [ABSTRACT FROM AUTHOR]

Pancreatic cancer is characterized by late detection, frequent drug resistance, and a highly metastatic nature, leading to poor prognosis. Antibody-based immunotherapy showed limited success for pancreatic cancer, partly owing to the low delivery rate of the drug into the tumor. Herein, we describe a poly(lactic-co-glycolic acid;PLGA)-based siRNA nanoparticle targeting PD-L1 (siPD-L1@PLGA). The siPD-L1@PLGA exhibited efficient knockdown of PD-L1 in cancer cells, without affecting the cell viability up to 6 mg/mL. Further, 99.2% of PDAC cells uptake the nanoparticle and successfully blocked the IFN-gamma-mediated PD-L1 induction. Consistently, the siPD-L1@PLGA sensitized cancer cells to antigen-specific immune cells, as exemplified by Ovalbumin-targeting T cells. To evaluate its efficacy in vivo, we adopted a pancreatic PDX model in humanized mice, generated by grafting CD34+ hematopoeitic stem cells onto NSG mice. The siPD-L1@PLGA significantly suppressed pancreatic tumor growth in this model with upregulated IFN-gamma positive CD8 T cells, leading to more apoptotic tumor cells. Multiplex immunofluorescence analysis exhibited comparable immune cell compositions in control and siPD-L1@PLGA-treated tumors. However, we found higher Granzyme B expression in the siPD-L1@PLGA-treated tumors, suggesting higher activity of NK or cytotoxic T cells. Based on these results, we propose the application of siPD-L1@PLGA as an immunotherapeutic agent for pancreatic cancer. [ABSTRACT FROM AUTHOR]

Tissue-resident memory T (TRM) cells with potent antiviral and antibacterial functions protect the epithelial and mucosal surfaces of our bodies against infection with pathogens. The strong proinflammatory activities of TRM cells suggest requirement for expression of inhibitory molecules to restrain these memory T cells under steady state conditions. We previously identified the adhesion G protein-coupled receptor GPR56 as an inhibitory receptor of human cytotoxic lymphocytes that regulates their cytotoxic effector functions. Here, we explored the expression pattern, expression regulation, and function of GPR56 on pathogen-specific CD8+ T cells using two infection models. We observed that GPR56 is expressed on TRM cells during acute infection and is upregulated by the TRM cell-inducing cytokine TGF-β and the TRM cell-associated transcription factor Hobit. However, GPR56 appeared dispensable for CD8+ T-cell differentiation and function upon acute infection with LCMV as well as Listeria monocytogenes. Thus, TRM cells specifically acquire the inhibitory receptor GPR56, but the impact of this receptor on TRM cells after acute infection does not appear essential to regulate effector functions of TRM cells. [ABSTRACT FROM AUTHOR]

Infection with the hepatitis E virus (HEV) is one of the main ubiquitous causes for developing an acute hepatitis. Moreover, chronification plays a predominant role in immunocompromised patients such as transplant recipients with more frequent severe courses. Unfortunately, besides reduction of immunosuppression and off-label use of ribavirin or pegylated interferon alfa, there is currently no specific anti-viral treatment to prevent disease progression. So far, research on involved immune mechanisms induced by HEV is limited. It is very difficult to collect clinical samples especially from the early phase of infection since this is often asymptomatic. Nevertheless, it is certain that the outcome of HEV-infected patients correlates with the strength of the proceeding immune response. Several lymphoid cells have been identified in contributing either to disease progression or achieving sustained virologic response. In particular, a sufficient immune control by both CD4+ and CD8+ T cells is necessary to prevent chronic viral replication. Especially the mechanisms underlying fulminant courses are poorly understood. However, liver biopsies indicate the involvement of cytotoxic T cells in liver damage. In this review, we aimed to highlight different parts of the lymphoid immune response against HEV and point out questions that remain unanswered regarding this underestimated global threat. [ABSTRACT FROM AUTHOR]

Trogocytosis is the intercellular transfer of membrane and membrane-associated molecules. This underappreciated process has been described in a variety of biological settings including neuronal remodeling, fertilization, viral and bacterial spread, and cancer, but has been most widely studied in cells of the immune system. Trogocytosis is performed by multiple immune cell types, including basophils, macrophages, dendritic cells, neutrophils, natural killer cells, B cells, γδ T cells, and CD4+ and CD8+ αβ T cells. Although not expressed endogenously, the presence of trogocytosed molecules on cells has the potential to significantly impact an immune response and the biology of the individual trogocytosis-positive cell. Many studies have focused on the ability of the trogocytosis-positive cells to interact with other immune cells and modulate the function of responders. Less understood and arguably equally important is the impact of these molecules on the individual trogocytosis-positive cell. Molecules that have been reported to be trogocytosed by cells include cognate ligands for receptors on the individual cell, such as activating NK cell ligands and MHC:peptide. These trogocytosed molecules have been shown to interact with receptors on the trogocytosis-positive cell and mediate intracellular signaling. In this review, we discuss the impact of this trogocytosis-mediated signaling on the biology of the individual trogocytosis-positive cell by focusing on natural killer cells and CD4+ T lymphocytes. [ABSTRACT FROM AUTHOR]

The development and progression of osteoarthritis (OA) is associated with macrophage-mediated inflammation that generates a broad spectrum of cytokines and reactive oxygen species (ROS). This study investigates the effects of mid-MW hyaluronic acid (HA) in combination with a lactose-modified chitosan (CTL), on pro-inflammatory molecules and metalloproteinases (MMPs) expression, using an in vitro model of macrophage-mediated inflammation. Methods. To assess chondrocyte response to HA and CTL in the presence of macrophage derived inflammatory mediators, cells were exposed to the conditioned medium (CM) of U937 activated monocytes and changes in cell viability, pro-inflammatory mediators and MMPs expression or ROS generation were analysed. Results. CTL induced changes in chondrocyte viability that are reduced by the presence of HA. The CM of activated U937 monocytes (macrophages) significantly increased gene expression of pro-inflammatory molecules and MMPs and intracellular ROS generation in human chondrocyte cultures. HA, CTL and their combinations counteracted the oxidative damage and restored gene transcription for IL-1β, TNF-α, Gal-1, MMP-3 and MMP-13 to near baseline values. Conclusions. This study suggests that HA-CTL mixture attenuated macrophage-induced inflammation, inhibited MMPs expression and exhibited anti-oxidative effects. This evidence provides an initial step toward the development of an early stage OA therapeutic treatment [ABSTRACT FROM AUTHOR]

The concept of innate lymphoid cells (ILCs) includes both conventional natural killer (NK) cells and helper ILCs, which resemble CD8+ killer T cells and CD4+ helper T cells in acquired immunity, respectively. Conventional NK cells are migratory cytotoxic cells that find tumor cells or cells infected with microbes. Helper ILCs are localized at peripheral tissue and are responsible for innate helper-cytokine production. Helper ILCs are classified into three subpopulations: TH1-like ILC1s, TH2-like ILC2s, and TH17/TH22-like ILC3s. Because of the functional similarities between ILCs and T cells, ILCs can serve as an innate component that augments each corresponding type of acquired immunity. However, the physiological functions of ILCs are more plastic and complicated than expected and are affected by environmental cues and types of inflammation. Here, we review recent advances in understanding the interaction between ILCs and acquired immunity, including T- and B-cell responses at various conditions. Immune suppressive activities by ILCs in particular are discussed in comparison to their immune stimulatory effects to gain precise knowledge of ILC biology and the physiological relevance of ILCs in human diseases. [ABSTRACT FROM AUTHOR]

The search for epitopes that will effectively trigger an immune response remains the "El Dorado" for immunologists. The development of promising immunotherapeutic approaches requires the appropriate targets to elicit a proper immune response. Considering the high degree of HLA/TCR diversity, as well as the heterogeneity of viral and tumor proteins, this number will invariably be higher than ideal to test. It is known that the recognition of a peptide-MHC (pMHC) by the T-cell receptor is performed entirely in a structural fashion, where the atomic interactions of both structures, pMHC and TCR, dictate the fate of the process. However, epitopes with a similar composition of amino acids can produce dissimilar surfaces. Conversely, sequences with no conspicuous similarities can exhibit similar TCR interaction surfaces. In the last decade, our group developed a database and in silico structural methods to extract molecular fingerprints that trigger T-cell immune responses, mainly referring to physicochemical similarities, which could explain the immunogenic differences presented by different pMHC-I complexes. Here, we propose an immunoinformatic approach that considers a structural level of information, combined with an experimental technology that simulates the presentation of epitopes for a T cell, to improve vaccine production and immunotherapy efficacy. [ABSTRACT FROM AUTHOR]