Showing papers on "Antibody published in 2018"
TL;DR: New-generation combinatorial therapies may overcome resistance mechanisms to immune checkpoint therapy, and evidence points to alterations that converge on the antigen presentation and interferon-γ signaling pathways.
Abstract: The release of negative regulators of immune activation (immune checkpoints) that limit antitumor responses has resulted in unprecedented rates of long-lasting tumor responses in patients with a variety of cancers. This can be achieved by antibodies blocking the cytotoxic T lymphocyte–associated protein 4 (CTLA-4) or the programmed cell death 1 (PD-1) pathway, either alone or in combination. The main premise for inducing an immune response is the preexistence of antitumor T cells that were limited by specific immune checkpoints. Most patients who have tumor responses maintain long-lasting disease control, yet one-third of patients relapse. Mechanisms of acquired resistance are currently poorly understood, but evidence points to alterations that converge on the antigen presentation and interferon-γ signaling pathways. New-generation combinatorial therapies may overcome resistance mechanisms to immune checkpoint therapy.
3,736 citations
TL;DR: NKG2A targeting with monalizumab is thus a novel checkpoint inhibitory mechanism promoting anti-tumor immunity by enhancing the activity of both T and NK cells, which may complement first-generation immunotherapies against cancer.
709 citations
TL;DR: Antibodies play an essential role in host defence against pathogens by recognizing microorganisms or infected cells as mentioned in this paper, and they can control and eradicate infections through a variety of other mechanisms.
Abstract: Antibodies play an essential role in host defence against pathogens by recognizing microorganisms or infected cells. Although preventing pathogen entry is one potential mechanism of protection, antibodies can control and eradicate infections through a variety of other mechanisms. In addition to binding and directly neutralizing pathogens, antibodies drive the clearance of bacteria, viruses, fungi and parasites via their interaction with the innate and adaptive immune systems, leveraging a remarkable diversity of antimicrobial processes locked within our immune system. Specifically, antibodies collaboratively form immune complexes that drive sequestration and uptake of pathogens, clear toxins, eliminate infected cells, increase antigen presentation and regulate inflammation. The diverse effector functions that are deployed by antibodies are dynamically regulated via differential modification of the antibody constant domain, which provides specific instructions to the immune system. Here, we review mechanisms by which antibody effector functions contribute to the balance between microbial clearance and pathology and discuss tractable lessons that may guide rational vaccine and therapeutic design to target gaps in our infectious disease armamentarium.
462 citations
TL;DR: Accumulating evidence demonstrates that the frequency and immunosuppressive function of MDSC in cancer patients can be used as a predictive marker for therapy response, and combination strategies for M DSC targeting together with ICI are provided to improve their therapeutic efficiency incancer patients.
Abstract: Immune checkpoint inhibitors (ICI) used for cancer immunotherapy were shown to boost the existing anti-tumor immune response by preventing the inhibition of T cells by tumor cells. Antibodies targeting two negative immune checkpoint pathways, namely cytotoxic T-lymphocyte-associated protein 4 (CTLA-4), programmed cell death protein 1 (PD-1), and programmed cell death-ligand 1 (PD-L1), have been approved first for patients with melanoma, squamous non-small cell lung cancer (NSCLC), and renal cell carcinoma. Clinical trials are ongoing to verify the efficiency of these antibodies for other cancer types and to evaluate strategies to block other checkpoint molecules. However, a number of patients do not respond to this treatment possibly due to profound immunosuppression, which is mediated partly by myeloid-derived suppressor cells (MDSC). This heterogeneous population of immature myeloid cells can strongly inhibit anti-tumor activities of T and NK cells and stimulate regulatory T cells (Treg), leading to tumor progression. Moreover, MDSC can contribute to patient resistance to immune checkpoint inhibition. Accumulating evidence demonstrates that the frequency and immunosuppressive function of MDSC in cancer patients can be used as a predictive marker for therapy response. This review focuses on the role of MDSC in immune checkpoint inhibition and provides an analysis of combination strategies for MDSC targeting together with ICI to improve their therapeutic efficiency in cancer patients.
363 citations
TL;DR: Targeting protein glycosylation as a potential strategy to enhance immune checkpoint therapy is suggested, as it remains largely unknown whether the sugar moiety contributes to immunosuppression.
335 citations
TL;DR: A recently developed vaccine platform, nucleoside-modified, purified mRNA encapsulated in lipid nanoparticles (mRNA-LNPs), that induces high levels of Tfh and GC B cells that are associated with long-lived and high-affinity neutralizing antibodies and durable protection.
Abstract: T follicular helper (Tfh) cells are required to develop germinal center (GC) responses and drive immunoglobulin class switch, affinity maturation, and long-term B cell memory. In this study, we characterize a recently developed vaccine platform, nucleoside-modified, purified mRNA encapsulated in lipid nanoparticles (mRNA-LNPs), that induces high levels of Tfh and GC B cells. Intradermal vaccination with nucleoside-modified mRNA-LNPs encoding various viral surface antigens elicited polyfunctional, antigen-specific, CD4+ T cell responses and potent neutralizing antibody responses in mice and nonhuman primates. Importantly, the strong antigen-specific Tfh cell response and high numbers of GC B cells and plasma cells were associated with long-lived and high-affinity neutralizing antibodies and durable protection. Comparative studies demonstrated that nucleoside-modified mRNA-LNP vaccines outperformed adjuvanted protein and inactivated virus vaccines and pathogen infection. The incorporation of noninflammatory, modified nucleosides in the mRNA is required for the production of large amounts of antigen and for robust immune responses.
319 citations
TL;DR: It is demonstrated that self-reactivity, defined as “autoproliferation” of peripheral Th1 cells, is elevated in patients carrying the HLA-DR15 haplotype, and RASGRP2 is identified as target autoantigen that is expressed in the brain and B cells.
303 citations
TL;DR: A combination therapy in multiple types of mouse cancer models that could provide sustainable antitumor immunity and led to shrinkage of distant tumors and long-term survival of the animals, even in a stringent spontaneous tumor model is investigated.
Abstract: It has recently become apparent that the immune system can cure cancer In some of these strategies, the antigen targets are preidentified and therapies are custom-made against these targets In others, antibodies are used to remove the brakes of the immune system, allowing preexisting T cells to attack cancer cells We have used another noncustomized approach called in situ vaccination Immunoenhancing agents are injected locally into one site of tumor, thereby triggering a T cell immune response locally that then attacks cancer throughout the body We have used a screening strategy in which the same syngeneic tumor is implanted at two separate sites in the body One tumor is then injected with the test agents, and the resulting immune response is detected by the regression of the distant, untreated tumor Using this assay, the combination of unmethylated CG–enriched oligodeoxynucleotide (CpG)—a Toll-like receptor 9 (TLR9) ligand—and anti-OX40 antibody provided the most impressive results TLRs are components of the innate immune system that recognize molecular patterns on pathogens Low doses of CpG injected into a tumor induce the expression of OX40 on CD4 + T cells in the microenvironment in mouse or human tumors An agonistic anti-OX40 antibody can then trigger a T cell immune response, which is specific to the antigens of the injected tumor Remarkably, this combination of a TLR ligand and an anti-OX40 antibody can cure multiple types of cancer and prevent spontaneous genetically driven cancers
291 citations
TL;DR: These antibodies inhibited tumor growth in multiple fully immunocompetent mouse models and reduced human melanoma metastases in a humanized mouse model and reactivates antitumor immunity.
Abstract: MICA and MICB are expressed by many human cancers as a result of cellular stress, and can tag cells for elimination by cytotoxic lymphocytes through natural killer group 2D (NKG2D) receptor activation. However, tumors evade this immune recognition pathway through proteolytic shedding of MICA and MICB proteins. We rationally designed antibodies targeting the MICA α3 domain, the site of proteolytic shedding, and found that these antibodies prevented loss of cell surface MICA and MICB by human cancer cells. These antibodies inhibited tumor growth in multiple fully immunocompetent mouse models and reduced human melanoma metastases in a humanized mouse model. Antitumor immunity was mediated mainly by natural killer (NK) cells through activation of NKG2D and CD16 Fc receptors. This approach prevents the loss of important immunostimulatory ligands by human cancers and reactivates antitumor immunity.
283 citations
TL;DR: How immune system, especially innate immune system and critical molecules are involved in the antiviral defense against IAVs is discussed and how IAV's antagonize different immune responses to achieve a successful infection is highlighted.
Abstract: Influenza A viruses (IAVs) are contagious pathogens responsible for severe respiratory infection in humans and animals worldwide. Upon detection of IAV infection, host immune system aims to defend against and clear the viral infection. Innate immune system is comprised of physical barriers (mucus and collectins), various phagocytic cells, group of cytokines, interferons (IFNs), and IFN-stimulated genes, which provide first line of defense against IAV infection. The adaptive immunity is mediated by B cells and T cells, characterized with antigen-specific memory cells, capturing and neutralizing the pathogen. The humoral immune response functions through hemagglutinin-specific circulating antibodies to neutralize IAV. In addition, antibodies can bind to the surface of infected cells and induce antibody-dependent cell-mediated cytotoxicity or complement activation. Although there are neutralizing antibodies against the virus, cellular immunity also plays a crucial role in the fight against IAVs. On the other hand, IAVs have developed multiple strategies to escape from host immune surveillance for successful replication. In this review, we discuss how immune system, especially innate immune system and critical molecules are involved in the antiviral defense against IAVs. In addition, we highlight how IAVs antagonize different immune responses to achieve a successful infection.
280 citations
TL;DR: Cytokines that control the immune response were shown to have efficacy in preclinical murine cancer models and are being investigated clinically in combination therapy with checkpoint inhibitors, anticancer monoclonal antibodies to increase the antibody-dependent cellular cytotoxicity of these antibodies, antibody cytokine fusion proteins, and anti-CD40 to facilitate tumor-specific immune responses.
Abstract: Cytokines that control the immune response were shown to have efficacy in preclinical murine cancer models. Interferon (IFN)-α is approved for treatment of hairy cell leukemia, and interleukin (IL)-2 for the treatment of advanced melanoma and metastatic renal cancer. In addition, IL-12, IL-15, IL-21, and granulocyte macrophage colony-stimulating factor (GM-CSF) have been evaluated in clinical trials. However, the cytokines as monotherapy have not fulfilled their early promise because cytokines administered parenterally do not achieve sufficient concentrations in the tumor, are often associated with severe toxicities, and induce humoral or cellular checkpoints. To circumvent these impediments, cytokines are being investigated clinically in combination therapy with checkpoint inhibitors, anticancer monoclonal antibodies to increase the antibody-dependent cellular cytotoxicity (ADCC) of these antibodies, antibody cytokine fusion proteins, and anti-CD40 to facilitate tumor-specific immune responses.
TL;DR: Epitope-based and antibody lineage-based HIV-1 vaccine approaches are being readied for human clinical trials, with proof of principle achieved with select HIV- 1-neutralizing antibody lineages in human-gene knock-in mouse models.
TL;DR: Various antibody engineering efforts intended to improve efficacy and safety relative to the human IgG isotype are reviewed and proposed mechanisms by which engineering approaches led to modified interactions with immune components are discussed.
Abstract: Therapeutic monoclonal antibodies are among the most effective biotherapeutics to date. An important aspect of antibodies is their ability to bind antigen while at the same time recruit immune effector functions. The majority of approved recombinant monoclonal antibody therapies are of the human IgG1 subclass, which can engage both humoral and cellular components of the immune system. The wealth of information generated about antibodies has afforded investigators the ability to molecularly engineer antibodies to modulate effector functions. Here, we review various antibody engineering efforts intended to improve efficacy and safety relative to the human IgG isotype. Further, we will discuss proposed mechanisms by which engineering approaches led to modified interactions with immune components and provide examples of clinical studies using next generation antibodies.
TL;DR: M1NV injection can repolarize M2 TAMs to M1 macrophages and potentiate antitumor efficacy of the checkpoint inhibitor therapy, and this study indicates that M1NV injected mice suppressed tumor growth and injection of a combination of M1NVs and aPD-L1 further reduced the tumor size.
Abstract: Cancer immunotherapy modulates immune cells to induce antitumor immune responses. Tumors employ immune checkpoints to evade immune cell attacks. Immune checkpoint inhibitors such as anti-PD-L1 antibody (aPD-L1), which is being used clinically for cancer treatments, can block immune checkpoints so that the immune system can attack tumors. However, immune checkpoint inhibitor therapy may be hampered by polarization of macrophages within the tumor microenvironment (TME) into M2 tumor-associated macrophages (TAMs), which suppress antitumor immune responses and promote tumor growth by releasing anti-inflammatory cytokines and angiogenic factors. In this study, we used exosome-mimetic nanovesicles derived from M1 macrophages (M1NVs) to repolarize M2 TAMs to M1 macrophages that release pro-inflammatory cytokines and induce antitumor immune responses and investigated whether the macrophage repolarization can potentiate the anticancer efficacy of aPD-L1. M1NV treatment induced successful polarization of M2 macrophages to M1 macrophages in vitro and in vivo. Intravenous injection of M1NVs into tumor-bearing mice suppressed tumor growth. Importantly, injection of a combination of M1NVs and aPD-L1 further reduced the tumor size, compared to the injection of either M1NVs or aPD-L1 alone. Thus, our study indicates that M1NV injection can repolarize M2 TAMs to M1 macrophages and potentiate antitumor efficacy of the checkpoint inhibitor therapy.
TL;DR: This Review discusses the key considerations and potential pitfalls of immune agonist antibody design and development, their differentiating features from antagonist antibodies and the landscape of agonist antibodies in clinical development for cancer treatment.
Abstract: Immune cell functions are regulated by co-inhibitory and co-stimulatory receptors. The first two generations of cancer immunotherapy agents consist primarily of antagonist antibodies that block negative immune checkpoints, such as programmed cell death protein 1 (PD1) and cytotoxic T lymphocyte protein 4 (CTLA4). Looking ahead, there is substantial promise in targeting co-stimulatory receptors with agonist antibodies, and a growing number of these agents are making their way through various stages of development. This Review discusses the key considerations and potential pitfalls of immune agonist antibody design and development, their differentiating features from antagonist antibodies and the landscape of agonist antibodies in clinical development for cancer treatment.
TL;DR: This study reveals that different combinations of TP53, EGFR, and STK11 mutations, together with PD-L1 expression by tumor cells, represent robust parameters to identify best responders to PD-1 blockade.
Abstract: Purpose: By unlocking antitumor immunity, antibodies targeting programmed cell death 1 (PD-1) exhibit impressive clinical results in non-small cell lung cancer, underlining the strong interactions between tumor and immune cells. However, factors that can robustly predict long-lasting responses are still needed.Experimental Design: We performed in-depth immune profiling of lung adenocarcinoma using an integrative analysis based on immunohistochemistry, flow-cytometry, and transcriptomic data. Tumor mutational status was investigated using next-generation sequencing. The response to PD-1 blockers was analyzed from a prospective cohort according to tumor mutational profiles and PD-L1 expression, and a public clinical database was used to validate the results obtained.Results: We showed that distinct combinations of STK11, EGFR, and TP53 mutations were major determinants of the tumor immune profile (TIP) and of the expression of PD-L1 by malignant cells. Indeed, the presence of TP53 mutations without co-occurring STK11 or EGFR alterations (TP53-mut/STK11-EGFR-WT), independently of KRAS mutations, identified the group of tumors with the highest CD8 T-cell density and PD-L1 expression. In this tumor subtype, pathways related to T-cell chemotaxis, immune cell cytotoxicity, and antigen processing were upregulated. Finally, a prolonged progression-free survival (PFS: HR = 0.32; 95% CI, 0.16-0.63, P < 0.001) was observed in anti-PD-1-treated patients harboring TP53-mut/STK11-EGFR-WT tumors. This clinical benefit was even more remarkable in patients with associated strong PD-L1 expression.Conclusions: Our study reveals that different combinations of TP53, EGFR, and STK11 mutations, together with PD-L1 expression by tumor cells, represent robust parameters to identify best responders to PD-1 blockade. Clin Cancer Res; 24(22); 5710-23. ©2018 AACR.
TL;DR: Findings indicate that NKG2A-blocking antibodies might improve clinical responses to therapeutic cancer vaccines and suggest an adaptive resistance mechanism to cancer vaccination.
TL;DR: It is demonstrated that neutrophils can exert a mode of destruction of cancer cells, which involves antibody-mediated trogocytosis by neutrophil, which can be further improved by targeting CD47-SIRPα interactions.
TL;DR: The mechanisms which enable the generation of potent protective humoral immunity whilst GC-derived autoimmunity is avoided are discussed, in both secondary lymphoid tissues, and Peyer's patches.
Abstract: The germinal center (GC) is a specialized microstructure that forms in secondary lymphoid tissues, producing long-lived antibody secreting plasma cells and memory B cells, which can provide protection against reinfection. Within the GC, B cells undergo somatic mutation of the genes encoding their B cell receptors which, following successful selection, can lead to the emergence of B cell clones that bind antigen with high affinity. However, this mutation process can also be dangerous, as it can create autoreactive clones that can cause autoimmunity. Because of this, regulation of GC reactions is critical to ensure high affinity antibody production and to enforce self-tolerance by avoiding emergence of autoreactive B cell clones. A productive GC response requires the collaboration of multiple cell types. The stromal cell network orchestrates GC cell dynamics by controlling antigen delivery and cell trafficking. T follicular helper (Tfh) cells provide specialized help to GC B cells through cognate T-B cell interactions while Foxp3+ T follicular regulatory (Tfr) cells are key mediators of GC regulation. However, regulation of GC responses is not a simple outcome of Tfh/Tfr balance, but also involves the contribution of other cell types to modulate the GC microenvironment and to avoid autoimmunity. Thus, the regulation of the GC is complex, and occurs at multiple levels. In this review we outline recent developments in the biology of cell subsets involved in the regulation of GC reactions, in both secondary lymphoid tissues, and Peyer's patches (PPs). We discuss the mechanisms which enable the generation of potent protective humoral immunity whilst GC-derived autoimmunity is avoided.
TL;DR: The relevance of antibody core fucosylation to ADCC is discussed, different strategies to produce afucosyated antibodies, and an update of afucOSylated antibody drugs currently undergoing clinical trials as well as those that have been approved are discussed.
Abstract: Therapeutic monoclonal antibodies are the fastest growing class of biological therapeutics for the treatment of various cancers and inflammatory disorders. In cancer immunotherapy, some IgG1 antibodies rely on the Fc-mediated immune effector function, antibody-dependent cellular cytotoxicity (ADCC), as the major mode of action to deplete tumor cells. It is well-known that this effector function is modulated by the N-linked glycosylation in the Fc region of the antibody. In particular, absence of core fucose on the Fc N-glycan has been shown to increase IgG1 Fc binding affinity to the FcγRIIIa present on immune effector cells such as natural killer cells and lead to enhanced ADCC activity. As such, various strategies have focused on producing afucosylated antibodies to improve therapeutic efficacy. This review discusses the relevance of antibody core fucosylation to ADCC, different strategies to produce afucosylated antibodies, and an update of afucosylated antibody drugs currently undergoing clinical trials as well as those that have been approved.
TL;DR: It was found that HBsAg-specific B cells persisted in the blood and liver of many patients with CHB and were enriched for T-bet, a signature of antiviral potential in B cells, however, purified, differentiated HBs Ag- specific B cells from patients withCHB had defective antibody production, consistent with undetectable anti-HBs antibodies in vivo.
Abstract: B cells are increasingly recognized as playing an important role in the ongoing control of hepatitis B virus (HBV). The development of antibodies against the viral surface antigen (HBV surface antigen [HBsAgs]) constitutes the hallmark of resolution of acute infection and is a therapeutic goal for functional cure of chronic HBV (CHB). We characterized B cells directly ex vivo from the blood and liver of patients with CHB to investigate constraints on their antiviral potential. Unexpectedly, we found that HBsAg-specific B cells persisted in the blood and liver of many patients with CHB and were enriched for T-bet, a signature of antiviral potential in B cells. However, purified, differentiated HBsAg-specific B cells from patients with CHB had defective antibody production, consistent with undetectable anti-HBs antibodies in vivo. HBsAg-specific and global B cells had an accumulation of CD21-CD27- atypical memory B cells (atMBC) with high expression of inhibitory receptors, including PD-1. These atMBC demonstrated altered signaling, homing, differentiation into antibody-producing cells, survival, and antiviral/proinflammatory cytokine production that could be partially rescued by PD-1 blockade. Analysis of B cells within healthy and HBV-infected livers implicated the combination of this tolerogenic niche and HBV infection in driving PD-1hiatMBC and impairing B cell immunity.
TL;DR: Improved understanding of modes of action and mechanisms of resistance has resulted in rationally designed CD38-based combination therapies, which will contribute to further improvement in outcome of MM patients.
Abstract: MM cells express high levels of CD38, while CD38 is expressed at relatively low levels on normal lymphoid and myeloid cells, and in some non-hematopoietic tissues. This expression profile, together with the role of CD38 in adhesion and as ectoenzyme, resulted in the development of CD38 antibodies for the treatment of multiple myeloma (MM). At this moment several CD38 antibodies are at different phases of clinical testing, with daratumumab already approved for various indications both as monotherapy and in combination with standards of care in MM. CD38 antibodies have Fc-dependent immune effector mechanisms, such as complement-dependent cytotoxicity (CDC), antibody-dependent cellular cytotoxicity (ADCC), and antibody-dependent cellular phagocytosis (ADCP). Inhibition of ectoenzymatic function and direct apoptosis induction may also contribute to the efficacy of the antibodies to kill MM cells. The CD38 antibodies also improve host-anti-tumor immunity by the elimination of regulatory T cells, regulatory B cells, and myeloid-derived suppressor cells. Mechanisms of primary and/or acquired resistance include tumor-related factors, such as reduced cell surface expression levels of the target antigen and high levels of complement inhibitors (CD55 and CD59). Differences in frequency or activity of effector cells may also contribute to differences in outcome. Furthermore, the microenvironment protects MM cells to CD38 antibody-induced ADCC by upregulation of anti-apoptotic molecules, such as survivin. Improved understanding of modes of action and mechanisms of resistance has resulted in rationally designed CD38-based combination therapies, which will contribute to further improvement in outcome of MM patients.
TL;DR: It is suggested that a rational design of universal vaccines needs to consider circulating TFH cells, preexisting serological memory, and tissue compartmentalization for effective B cell immunity, as well as to improve targeting cellular T cell immunity.
Abstract: Immunization with the inactivated influenza vaccine (IIV) remains the most effective strategy to combat seasonal influenza infections IIV activates B cells and T follicular helper (TFH) cells and thus engenders antibody-secreting cells and serum antibody titers However, the cellular events preceding generation of protective immunity in humans are inadequately understood We undertook an in-depth analysis of B cell and T cell immune responses to IIV in 35 healthy adults Using recombinant hemagglutinin (rHA) probes to dissect the quantity, phenotype, and isotype of influenza-specific B cells against A/California09-H1N1, A/Switzerland-H3N2, and B/Phuket, we showed that vaccination induced a three-pronged B cell response comprising a transient CXCR5-CXCR3+ antibody-secreting B cell population, CD21hiCD27+ memory B cells, and CD21loCD27+ B cells Activation of circulating TFH cells correlated with the development of both CD21lo and CD21hi memory B cells However, preexisting antibodies could limit increases in serum antibody titers IIV had no marked effect on CD8+, mucosal-associated invariant T, γδ T, and natural killer cell activation In addition, vaccine-induced B cells were not maintained in peripheral blood at 1 year after vaccination We provide a dissection of rHA-specific B cells across seven human tissue compartments, showing that influenza-specific memory (CD21hiCD27+) B cells primarily reside within secondary lymphoid tissues and the lungs Our study suggests that a rational design of universal vaccines needs to consider circulating TFH cells, preexisting serological memory, and tissue compartmentalization for effective B cell immunity, as well as to improve targeting cellular T cell immunity
TL;DR: A family of Chimeric Antigen Receptors for Phagocytosis (CAR-Ps) that direct macrophages to engulf specific targets, including cancer cells, are engineered and show that CAR-Ps drive specific engulfment of antigen-coated synthetic particles and whole human cancer cells.
Abstract: Chimeric antigen receptors (CARs) are synthetic receptors that reprogram T cells to kill cancer. The success of CAR-T cell therapies highlights the promise of programmed immunity and suggests that applying CAR strategies to other immune cell lineages may be beneficial. Here, we engineered a family of Chimeric Antigen Receptors for Phagocytosis (CAR-Ps) that direct macrophages to engulf specific targets, including cancer cells. CAR-Ps consist of an extracellular antibody fragment, which can be modified to direct CAR-P activity towards specific antigens. By screening a panel of engulfment receptor intracellular domains, we found that the cytosolic domains from Megf10 and FcRɣ robustly triggered engulfment independently of their native extracellular domain. We show that CAR-Ps drive specific engulfment of antigen-coated synthetic particles and whole human cancer cells. Addition of a tandem PI3K recruitment domain increased cancer cell engulfment. Finally, we show that CAR-P expressing murine macrophages reduce cancer cell number in co-culture by over 40%.
TL;DR: This work shows an upregulation of Siglecs, including Siglec-9, on tumor-infiltrating T cells from non–small cell lung cancer, colorectal, and ovarian cancer patients and identifies the sialoglycan-SAMP/Siglec pathway as a potential target for improving T cell activation for immunotherapy.
Abstract: First-generation immune checkpoint inhibitors, including anti-CTLA-4 and anti-programmed death 1 (anti-PD-1) antibodies, have led to major clinical progress, yet resistance frequently leads to treatment failure. Thus, new targets acting on T cells are needed. CD33-related sialic acid-binding immunoglobulin-like lectins (Siglecs) are pattern-recognition immune receptors binding to a range of sialoglycan ligands, which appear to function as self-associated molecular patterns (SAMPs) that suppress autoimmune responses. Siglecs are expressed at very low levels on normal T cells, and these receptors were not until recently considered as interesting targets on T cells for cancer immunotherapy. Here, we show an upregulation of Siglecs, including Siglec-9, on tumor-infiltrating T cells from non-small cell lung cancer (NSCLC), colorectal, and ovarian cancer patients. Siglec-9-expressing T cells coexpressed several inhibitory receptors, including PD-1. Targeting of the sialoglycan-SAMP/Siglec pathway in vitro and in vivo resulted in increased anticancer immunity. T cell expression of Siglec-9 in NSCLC patients correlated with reduced survival, and Siglec-9 polymorphisms showed association with the risk of developing lung and colorectal cancer. Our data identify the sialoglycan-SAMP/Siglec pathway as a potential target for improving T cell activation for immunotherapy.
TL;DR: This study isolated IgM and IgG monoclonal antibodies from Tanzanian volunteers who were immunized with repeated injection of Sanaria PfSPZ Vaccine and who were found to be protected from controlled human malaria infection with infectious homologous PfSPzs.
Abstract: Immunization with attenuated Plasmodium falciparum sporozoites (PfSPZs) has been shown to be protective against malaria, but the features of the antibody response induced by this treatment remain unclear. To investigate this response in detail, we isolated IgM and IgG monoclonal antibodies from Tanzanian volunteers who were immunized with repeated injection of Sanaria PfSPZ Vaccine and who were found to be protected from controlled human malaria infection with infectious homologous PfSPZs. All isolated IgG monoclonal antibodies bound to P. falciparum circumsporozoite protein (PfCSP) and recognized distinct epitopes in its N terminus, NANP-repeat region, and C terminus. Strikingly, the most effective antibodies, as determined in a humanized mouse model, bound not only to the repeat region, but also to a minimal peptide at the PfCSP N-terminal junction that is not in the RTS,S vaccine. These dual-specific antibodies were isolated from different donors and were encoded by VH3-30 or VH3-33 alleles that encode tryptophan or arginine at position 52. Using structural and mutational data, we describe the elements required for germline recognition and affinity maturation. Our study provides potent neutralizing antibodies and relevant information for lineage-targeted vaccine design and immunization strategies.
TL;DR: This study develops a Bcl6fl/flFoxp3Cre mouse and indicates that Tfr cells control autoimmune diseases and can be targeted in infectious and autoimmune disease.
Abstract: T follicular regulatory (Tfr) cells are a new subset of regulatory T (T reg) cells localized in the germinal center to limit the humoral response. Until now, the physiological function of Tfr cells has been largely unknown. In this study, we developed a Bcl6fl/flFoxp3Cre mouse to analyze the function of Tfr cells in immune and autoimmune responses. These mice exhibited enhanced immunity to influenza virus; moreover, Bcl6fl/flFoxp3Cre/Cre mice developed late-onset spontaneous autoimmune diseases, affecting the salivary glands with lymphocyte infiltration and antibody deposition. In a mouse experimental Sjogren's syndrome model, ablation of Bcl6 in T reg cells greatly enhanced disease development. Conversely, Bcl6fl/flCd4Cre mice were protected in the model. Thus, our study indicates that Tfr cells control autoimmune diseases and can be targeted in infectious and autoimmune disease.
TL;DR: Tissue-resident memory T (TRM) cells appear to represent important components in tumor immune surveillance and are correlated with better clinical outcome in both univariate and multivariate analyses independently of CD8+ T cells.
Abstract: CD8+ T lymphocytes are the major anti-tumor effector cells Most cancer immunotherapeutic approaches seek to amplify cytotoxic T lymphocytes (CTL) specific to malignant cells A recently identified subpopulation of memory CD8+ T cells, named tissue-resident memory T (TRM) cells, persists in peripheral tissues and does not recirculate This T-cell subset is considered an independent memory T-cell lineage with a specific profile of transcription factors, including Runx3+, Notch+, Hobit+, Blimp1+, BATF+, AHR+, EOMESneg and Tbetlow It is defined by expression of CD103 (αE(CD103)β7) and CD49a (VLA-1 or α1β1) integrins and C-type lectin CD69, which are most likely involved in retention of TRM cells in non-lymphoid tissues, including solid tumors CD103 binds to the epithelial cell marker E-cadherin, thereby favoring the location and retention of TRM in epithelial tumor regions in close contact with malignant cells The CD103-E-cadherin interaction is required for polarized exocytosis of lytic granules, in particular, when ICAM-1 expression on cancer cells is missing, leading to target cell death TRM cells also express high levels of granzyme B, IFNγ and TNFα, supporting their cytotoxic features Moreover, the local route of immunization targeting tissue dendritic cells (DC), and the presence of environmental factors (ie TGF-β, IL-33 and IL-15), promote differentiation of this T-cell subtype In both spontaneous tumor models and engrafted tumors, natural TRM cells or cancer-vaccine-induced TRM directly control tumor growth In line with these results, TRM infiltration into various human cancers, including lung cancer, are correlated with better clinical outcome in both univariate and multivariate analyses independently of CD8+ T cells TRM cells also predominantly express checkpoint receptors such as PD-1, CTLA-4 and Tim-3 Blockade of PD-1 with neutralizing antibodies on TRM cells isolated from human lung cancer promotes cytolytic activity toward autologous tumor cells Thus, TRM cells appear to represent important components in tumor immune surveillance Their induction by cancer vaccines or other immunotherapeutic approaches may be critical for the success of these treatments Several arguments, such as their close contact with tumor cells, dominant expression of checkpoint receptors and their recognition of cancer cells, strongly suggest that they may be involved in the success of immune checkpoint inhibitors in various cancers
Scripps Research Institute1, Ragon Institute of MGH, MIT and Harvard2, Albert Einstein College of Medicine3, University of Wisconsin-Madison4, United States Department of the Army5, Public Health Agency of Canada6, Los Alamos National Laboratory7, Emory University8, University of Texas Medical Branch9, Vanderbilt University Medical Center10, University of Texas at Austin11, Icahn School of Medicine at Mount Sinai12, Regeneron13, University of Oxford14, Hokkaido University15, University of Lyon16, Agency for Science, Technology and Research17, Laval University18
TL;DR: This comprehensive dataset provides a rubric to evaluate novel antibodies and vaccine responses and a roadmap for therapeutic development for EBOV and related viruses.
TL;DR: A method of characterizing polyclonal responses by using electron microscopy is described, and this method is applied to the immunization of rabbits with an HIV‐1 envelope glycoprotein vaccine candidate, BG505 SOSIP.