scispace - formally typeset
Search or ask a question

Showing papers on "Antigen published in 2011"


Journal ArticleDOI
TL;DR: A low dose of autologous chimeric antigen receptor-modified T cells reinfused into a patient with refractory chronic lymphocytic leukemia expanded to a level that was more than 1000 times as high as the initial engraftment level in vivo, with delayed development of the tumor lysis syndrome and with complete remission.
Abstract: We designed a lentiviral vector expressing a chimeric antigen receptor with specificity for the B-cell antigen CD19, coupled with CD137 (a costimulatory receptor in T cells [4-1BB]) and CD3-zeta (a signal-transduction component of the T-cell antigen receptor) signaling domains. A low dose (approximately 1.5×10(5) cells per kilogram of body weight) of autologous chimeric antigen receptor-modified T cells reinfused into a patient with refractory chronic lymphocytic leukemia (CLL) expanded to a level that was more than 1000 times as high as the initial engraftment level in vivo, with delayed development of the tumor lysis syndrome and with complete remission. Apart from the tumor lysis syndrome, the only other grade 3/4 toxic effect related to chimeric antigen receptor T cells was lymphopenia. Engineered cells persisted at high levels for 6 months in the blood and bone marrow and continued to express the chimeric antigen receptor. A specific immune response was detected in the bone marrow, accompanied by loss of normal B cells and leukemia cells that express CD19. Remission was ongoing 10 months after treatment. Hypogammaglobulinemia was an expected chronic toxic effect.

3,204 citations


Journal ArticleDOI
TL;DR: A timely evaluation of the biology of antigen presentation and a survey of issues that are considered unresolved are presented.
Abstract: The molecular details of antigen processing and presentation by MHC class I and class II molecules have been studied extensively for almost three decades. Although the basic principles of these processes were laid out approximately 10 years ago, the recent years have revealed many details and provided new insights into their control and specificity. MHC molecules use various biochemical reactions to achieve successful presentation of antigenic fragments to the immune system. Here we present a timely evaluation of the biology of antigen presentation and a survey of issues that are considered unresolved. The continuing flow of new details into our understanding of the biology of MHC class I and class II antigen presentation builds a system involving several cell biological processes, which is discussed in this Review.

1,571 citations


Journal ArticleDOI
TL;DR: It is shown that exosomes of T, B and dendritic immune cells contain microRNA (miRNA) repertoires that differ from those of their parent cells, and that miRNAs transferred during immune synapsis are able to modulate gene expression in recipient cells.
Abstract: The immune synapse is an exquisitely evolved means of communication between T cells and antigen-presenting cells (APCs) during antigen recognition. Recent evidence points to the transfer of RNA via exosomes as a novel mode of intercellular communication. Here we show that exosomes of T, B and dendritic immune cells contain microRNA (miRNA) repertoires that differ from those of their parent cells. We investigate whether miRNAs are exchanged during cognate immune interactions, and demonstrate the existence of antigen-driven unidirectional transfer of miRNAs from the T cell to the APC, mediated by the delivery of CD63+ exosomes on immune synapse formation. Inhibition of exosome production by targeting neutral sphingomyelinase-2 impairs transfer of miRNAs to APCs. Moreover, miRNAs transferred during immune synapsis are able to modulate gene expression in recipient cells. Thus, our results support a mechanism of cellular communication involving antigen-dependent, unidirectional intercellular transfer of miRNAs by exosomes during immune synapsis.

1,565 citations


Journal ArticleDOI
12 Aug 2011-Science
TL;DR: An antibody able to broadly neutralize both group 1 and group 2 influenza A viruses—and its target epitope—are identified and may be used for passive protection and to inform vaccine design because of its broad specificity and neutralization potency.
Abstract: The isolation of broadly neutralizing antibodies against influenza A viruses has been a long-sought goal for therapeutic approaches and vaccine design. Using a single-cell culture method for screening large numbers of human plasma cells, we isolated a neutralizing monoclonal antibody that recognized the hemagglutinin (HA) glycoprotein of all 16 subtypes and neutralized both group 1 and group 2 influenza A viruses. Passive transfer of this antibody conferred protection to mice and ferrets. Complexes with HAs from the group 1 H1 and the group 2 H3 subtypes analyzed by x-ray crystallography showed that the antibody bound to a conserved epitope in the F subdomain. This antibody may be used for passive protection and to inform vaccine design because of its broad specificity and neutralization potency.

1,146 citations


Journal ArticleDOI
01 Dec 2011-Blood
TL;DR: It is shown that GD2-CAR T cells can induce complete tumor responses in patients with active neuroblastoma; these CAR T cells may have extended, low-level persistence in patients, and such persistence was associated with longer survival.

957 citations


Journal ArticleDOI
24 Feb 2011-Nature
TL;DR: It is demonstrated that immunization of mice with synthetic nanoparticles containing antigens plus ligands that signal through TLR4 and TLR7 induces synergistic increases in antigen-specific, neutralizing antibodies compared to immunization with nanoparticles minus a single TLR ligand, and there was enhanced persistence of germinal centres and of plasma-cell responses, which persisted in the lymph nodes for >1.5 years.
Abstract: A feature of many successful vaccines is the induction of memory B cells and long-lived plasma cells that can secrete neutralizing antibodies for a lifetime. The mechanisms that stimulate such persistent responses remain poorly understood. Bali Pulendran and colleagues show that nanoparticles containing two Toll-like receptor ligands, proteins with important roles in innate immunity, can boost the magnitude and persistence of vaccine-elicited antibody responses in primates, improving vaccine-mediated protection against influenza virus. Here it is shown that nanoparticles containing two Toll-like receptor ligands can boost the magnitude and persistence of vaccine-elicited antibody responses in primates, improving vaccine-mediated protection against influenza virus. Many successful vaccines induce persistent antibody responses that can last a lifetime. The mechanisms by which they do so remain unclear, but emerging evidence indicates that they activate dendritic cells via Toll-like receptors (TLRs)1,2. For example, the yellow fever vaccine YF-17D, one of the most successful empiric vaccines ever developed3, activates dendritic cells via multiple TLRs to stimulate proinflammatory cytokines4,5. Triggering specific combinations of TLRs in dendritic cells can induce synergistic production of cytokines6, which results in enhanced T-cell responses, but its impact on antibody responses remain unknown. Learning the critical parameters of innate immunity that program such antibody responses remains a major challenge in vaccinology. Here we demonstrate that immunization of mice with synthetic nanoparticles containing antigens plus ligands that signal through TLR4 and TLR7 induces synergistic increases in antigen-specific, neutralizing antibodies compared to immunization with nanoparticles containing antigens plus a single TLR ligand. Consistent with this there was enhanced persistence of germinal centres and of plasma-cell responses, which persisted in the lymph nodes for >1.5 years. Surprisingly, there was no enhancement of the early short-lived plasma-cell response relative to that observed with single TLR ligands. Molecular profiling of activated B cells, isolated 7 days after immunization, indicated that there was early programming towards B-cell memory. Antibody responses were dependent on direct triggering of both TLRs on B cells and dendritic cells, as well as on T-cell help. Immunization protected completely against lethal avian and swine influenza virus strains in mice, and induced robust immunity against pandemic H1N1 influenza in rhesus macaques.

907 citations


Journal ArticleDOI
13 Oct 2011-Nature
TL;DR: The results suggest that the efficient peripheral generation of antigen-specific populations of Treg cells in response to an individual’s microbiota provides important post-thymic education of the immune system to foreign antigens, thereby providing tolerance to commensal microbiota.
Abstract: Understanding how the immune system becomes tolerant to foreign antigens from commensal bacteria is a fundamental question, as breakdown of tolerance can result in unwanted responses such as inflammatory bowel disease. It has been suggested that tolerogenic regulatory T (Treg) cells are generated in response to commensal bacteria, but there is little direct evidence to support this hypothesis. A study of the colonic T-cell antigen receptor repertoire of mice now shows that microbial antigens direct the generation of antigen-specific inducible Treg cells in the colon. Commensal-induced Treg cells seem to maintain mucosal tolerance and protect mice from colitis. The instruction of the immune system to be tolerant of self, thereby preventing autoimmunity, is facilitated by the education of T cells in a specialized organ, the thymus, in which self-reactive cells are either eliminated or differentiated into tolerogenic Foxp3+ regulatory T (Treg) cells1. However, it is unknown whether T cells are also educated to be tolerant of foreign antigens, such as those from commensal bacteria, to prevent immunopathology such as inflammatory bowel disease2,3,4. Here we show that encounter with commensal microbiota results in the peripheral generation of Treg cells rather than pathogenic effectors. We observed that colonic Treg cells used T-cell antigen receptors (TCRs) different from those used by Treg cells in other locations, implying an important role for local antigens in shaping the colonic Treg-cell population. Many of the local antigens seemed to be derived from commensal bacteria, on the basis of the in vitro reactivity of common colon Treg TCRs. These TCRs did not facilitate thymic Treg-cell development, implying that many colonic Treg cells arise instead by means of antigen-driven peripheral Treg-cell development. Further analysis of two of these TCRs by the creation of retroviral bone marrow chimaeras and a TCR transgenic line revealed that microbiota indigenous to our mouse colony was required for the generation of colonic Treg cells from otherwise naive T cells. If T cells expressing these TCRs fail to undergo Treg-cell development and instead become effector cells, they have the potential to induce colitis, as evidenced by adoptive transfer studies. These results suggest that the efficient peripheral generation of antigen-specific populations of Treg cells in response to an individual’s microbiota provides important post-thymic education of the immune system to foreign antigens, thereby providing tolerance to commensal microbiota.

888 citations


Journal ArticleDOI
TL;DR: Dendritic cell responsiveness to type I interferon is required for the generation of antitumor T cell responses and tumor rejection.
Abstract: Cancer immunoediting is the process whereby the immune system suppresses neoplastic growth and shapes tumor immunogenicity. We previously reported that type I interferon (IFN-α/β) plays a central role in this process and that hematopoietic cells represent critical targets of type I IFN’s actions. However, the specific cells affected by IFN-α/β and the functional processes that type I IFN induces remain undefined. Herein, we show that type I IFN is required to initiate the antitumor response and that its actions are temporally distinct from IFN-γ during cancer immunoediting. Using mixed bone marrow chimeric mice, we demonstrate that type I IFN sensitivity selectively within the innate immune compartment is essential for tumor-specific T cell priming and tumor elimination. We further show that mice lacking IFNAR1 (IFN-α/β receptor 1) in dendritic cells (DCs; Itgax-Cre+Ifnar1f/f mice) cannot reject highly immunogenic tumor cells and that CD8α+ DCs from these mice display defects in antigen cross-presentation to CD8+ T cells. In contrast, mice depleted of NK cells or mice that lack IFNAR1 in granulocytes and macrophage populations reject these tumors normally. Thus, DCs and specifically CD8α+ DCs are functionally relevant targets of endogenous type I IFN during lymphocyte-mediated tumor rejection.

866 citations


Journal ArticleDOI
26 Aug 2011-Immunity
TL;DR: Recent advances in CD8+ T cell recognition of antigen in lymphoid as well as in nonlymphoid tissues in the periphery are reviewed, and how CD8-T cell expansion and differentiation are controlled in these contexts are reviewed.

847 citations


Journal ArticleDOI
TL;DR: T cells engaged by blinatumomab seem capable of eradicating chemotherapy-resistant tumor cells that otherwise cause clinical relapse in patients with MRD-positive B-lineage ALL after intensive chemotherapy.
Abstract: Purpose Blinatumomab, a bispecific single-chain antibody targeting the CD19 antigen, is a member of a novel class of antibodies that redirect T cells for selective lysis of tumor cells. In acute lymphoblastic leukemia (ALL), persistence or relapse of minimal residual disease (MRD) after chemotherapy indicates resistance to chemotherapy and results in hematologic relapse. A phase II clinical study was conducted to determine the efficacy of blinatumomab in MRD-positive B-lineage ALL.

832 citations


Journal ArticleDOI
TL;DR: This report represents the first example of objective regression of metastatic colorectal cancer mediated by adoptive T cell transfer and illustrates the successful use of a TCR, raised in human leukocyte antigen (HLA) transgenic mice, against a human tumor associated antigen.

Journal ArticleDOI
25 Feb 2011-Immunity
TL;DR: A model of stepwise oral tolerance induction induction comprising the generation of Treg cells in the gut-draining lymph nodes, followed by migration into the gut and subsequent expansion of T Reg cells driven by intestinal macrophages is proposed.

Journal ArticleDOI
TL;DR: This Review highlights the many stages that an NK cell progresses through during its remarkable lifetime, discussing similarities and differences with its close relative, the cytotoxic CD8+ T cell.
Abstract: Natural killer (NK) cells survey host tissues for signs of infection, transformation or stress and, true to their name, kill target cells that have become useless or are detrimental to the host. For decades, NK cells have been classified as a component of the innate immune system. However, accumulating evidence in mice and humans suggests that, like the B and T cells of the adaptive immune system, NK cells are educated during development, possess antigen-specific receptors, undergo clonal expansion during infection and generate long-lived memory cells. In this Review, we highlight the many stages that an NK cell progresses through during its remarkable lifetime, discussing similarities and differences with its close relative, the cytotoxic CD8(+) T cell.

Journal ArticleDOI
28 Apr 2011-Blood
TL;DR: Combined PD-1/PDL1 and Tim-3/galectin-9 blockade may be beneficial in preventing CD8(+) T-cell exhaustion in patients with hematologic malignancies such as advanced AML.

Journal ArticleDOI
04 Aug 2011-Blood
TL;DR: It is shown that huEGFRt serves as a highly efficient selection epitope for chimeric antigen receptor(+) T cells using biotinylated cetuximab in conjunction with current good manufacturing practices (cGMP)-grade anti-biotin immunomagnetic microbeads.

Journal ArticleDOI
TL;DR: This work reports an extensive characterization of the therapeutic activity and mechanism of action of an anti-mouse TIM3 mAb against experimental and carcinogen-induced tumors, and for the first time defines the mechanism of antitumor action of anti-TIM3 requiring IFN-γ producing CD8(+) T cells and CD4(+) T cells correlating with therapeutic success.
Abstract: Strategies to activate and rescue exhausted tumor-specific T cells, including the use of monoclonal antibodies (mAb) that block the negative costimulatory receptors CTLA-4 and PD-1 are proving very effective, but TIM3 has been relatively neglected as a target. Here we report an extensive characterization of the therapeutic activity and mechanism of action of an anti-mouse TIM3 mAb against experimental and carcinogen-induced tumors. For the first time we specifically define the mechanism of antitumor action of anti-TIM3 requiring IFN-γ producing CD8(+) T cells and CD4(+) T cells, and a higher ratio of tumor infiltrating CD8(+):CD4(+) T cells correlating with therapeutic success. Interestingly, in some models, anti-TIM3 appeared to be effective sometime before the appearance and accumulation of significant TIM3(+)PD-1(+) T cell populations in tumor bearing mice. Anti-TIM3 displayed modest prophylactic and therapeutic activity against a small fraction of carcinogen-induced sarcomas, but comparative and combination studies of anti-TIM3 with anti-CTLA-4 and anti-PD-1 against experimental and carcinogen-induced tumors suggested that these agents might be well-tolerated and very effective in combination.

Journal ArticleDOI
TL;DR: These data support safety, immunogenicity, and preliminary clinical activity of poly-ICLC-boosted αDC1-based vaccines.
Abstract: Purpose A phase I/II trial was performed to evaluate the safety and immunogenicity of a novel vaccination with α-type 1 polarized dendritic cells (αDC1) loaded with synthetic peptides for glioma-associated antigen (GAA) epitopes and administration of polyinosinic-polycytidylic acid [poly(I:C)] stabilized by lysine and carboxymethylcellulose (poly-ICLC) in HLA-A2+ patients with recurrent malignant gliomas. GAAs for these peptides are EphA2, interleukin (IL)-13 receptor-α2, YKL-40, and gp100. Patients and Methods Twenty-two patients (13 with glioblastoma multiforme [GBM], five with anaplastic astrocytoma [AA], three with anaplastic oligodendroglioma [AO], and one with anaplastic oligoastrocytoma [AOA]) received at least one vaccination, and 19 patients received at least four vaccinations at two αDC1 dose levels (1 × or 3 × 107/dose) at 2-week intervals intranodally. Patients also received twice weekly intramuscular injections of 20 μg/kg poly-ICLC. Patients who demonstrated positive radiologic response or s...

Journal ArticleDOI
04 Mar 2011-Science
TL;DR: It is proposed that memory relies on swIg+ cells until they disappear and serum immunoglobulin falls to a low level, in which case memory resides with durable IgM+ reserves.
Abstract: Memory B cells formed in response to microbial antigens provide immunity to later infections; however, the inability to detect rare endogenous antigen-specific cells limits current understanding of this process. Using an antigen-based technique to enrich these cells, we found that immunization with a model protein generated B memory cells that expressed isotype-switched immunoglobulins (swIg) or retained IgM. The more numerous IgM(+) cells were longer lived than the swIg(+) cells. However, swIg(+) memory cells dominated the secondary response because of the capacity to become activated in the presence of neutralizing serum immunoglobulin. Thus, we propose that memory relies on swIg(+) cells until they disappear and serum immunoglobulin falls to a low level, in which case memory resides with durable IgM(+) reserves.

Journal ArticleDOI
TL;DR: Characterization of the molecular basis of the pathogenic mechanisms involved, including the putative second hits and the role of complement activation, might offer an answer to this question.
Abstract: Antiphospholipid antibodies (aPL) are both diagnostic markers for, and pathogenic drivers of, antiphospholipid syndrome (APS). Although the presence of aPL is a necessary pre-condition, APS-associated clotting is seemingly triggered by an additional 'second hit', frequently related to innate inflammatory immune responses. β(2) glycoprotein I (β(2)GPI)-dependent aPL, the most important subset of these antibodies, mediate several--not necessarily alternative--thrombogenic mechanisms, mainly on the basis of their reactivity with β(2)GPI expressed on the membrane of cells that participate in the coagulation cascade. Recurrent pregnancy complications associated with aPL cannot be explained solely by thrombosis, and alternative pathogenic mechanisms have been reported. Although one in vivo model of fetal loss suggests a mechanism of aPL-mediated acute placental inflammation, other models and the histopathological examination of APS placentae do not support a widespread inflammatory signature. β(2)GPI-dependent aPL are thought to recognize their antigen on placental tissues, inhibit the growth and differentiation of trophoblasts, and eventually cause defective placentation. Why antibodies with similar antigen specificity produce different clinical manifestations is not clear. Characterization of the molecular basis of the pathogenic mechanisms involved, including the putative second hits and the role of complement activation, might offer an answer to this question.

Journal ArticleDOI
TL;DR: The purpose of this review is to summarise the current knowledge of mucosal immunoglobulins and B cells of fish MALT, and attempt to integrate the existing knowledge on both basic and applied research findings on fish mucosal immune responses to provide new directions that may facilitate the development of novel vaccination strategies.
Abstract: As physical barriers that separate teleost fish from the external environment, mucosae are also active immunological sites that protect them against exposure to microbes and stressors. In mammals, the sites where antigens are sampled from mucosal surfaces and where stimulation of naive T and B lymphocytes occurs are known as inductive sites and are constituted by mucosa-associated lymphoid tissue (MALT). According to anatomical location, the MALT in teleost fish is subdivided into gut-associated lymphoid tissue (GALT), skin-associated lymphoid tissue (SALT), and gill-associated lymphoid tissue (GIALT). All MALT contain a variety of leukocytes, including, but not limited to, T cells, B cells, plasma cells, macrophages and granulocytes. Secretory immunoglobulins are produced mainly by plasmablasts and plasma cells, and play key roles in the maintenance of mucosal homeostasis. Until recently, teleost fish B cells were thought to express only two classes of immunoglobulins, IgM and IgD, in which IgM was thought to be the only one responding to pathogens both in systemic and mucosal compartments. However, a third teleost immunoglobulin class, IgT/IgZ, was discovered in 2005, and it has recently been shown to behave as the prevalent immunoglobulin in gut mucosal immune responses. The purpose of this review is to summarise the current knowledge of mucosal immunoglobulins and B cells of fish MALT. Moreover, we attempt to integrate the existing knowledge on both basic and applied research findings on fish mucosal immune responses, with the goal to provide new directions that may facilitate the development of novel vaccination strategies that stimulate not only systemic, but also mucosal immunity.

Journal ArticleDOI
TL;DR: Data show the presence of a unique autoantibody system recognizing carbamylated, but not citrullinated, protein antigens in the sera of rheumatoid arthritis patients, indicating that anti-CarP antibodies are a unique and relevant serological marker for ACPA-negative RA.
Abstract: Autoimmune responses against posttranslationally modified antigens are a hallmark of several autoimmune diseases. For example, antibodies against citrullinated protein antigens (ACPA) have shown their relevance for the prognosis and diagnosis of rheumatoid arthritis (RA), and have been implicated in disease pathogenesis. It is conceivable that other autoantibody systems, recognizing other posttranslationally modified proteins, are also present in RA. Here, we describe the presence of an autoantibody system that discriminates between citrulline- and homocitrulline-containing antigens in the sera of RA-patients. IgG antibodies recognizing carbamylated (homocitrulline-containing) antigens were present in sera of over 45% of RA-patients. Likewise, anticarbamylated protein (anti-CarP) IgA antibodies were observed in 43% of RA-sera. ACPA and anti-CarP antibodies are distinct autoantibodies because, in selected double-positive patients, the anti-CarP antibody binding to carbamylated antigens could be inhibited by carbamylated antigens, but not by control or citrullinated antigens. Similarly, ACPA-binding to citrullinated antigens could only be inhibited by citrullinated antigens. In line with this observation, 16% of ACPA-negative RA-patients, as measured by a standard ACPA assay, harbored IgG anti-CarP antibodies, whereas 30% of these patients tested positive for IgA anti-CarP antibodies. The presence of anti-CarP antibodies was predictive for a more severe disease course in ACPA-negative patients as measured by radiological progression. Taken together, these data show the presence of a unique autoantibody system recognizing carbamylated, but not citrullinated, protein antigens. These antibodies are predictive for a more severe clinical course in ACPA-negative RA-patients, indicating that anti-CarP antibodies are a unique and relevant serological marker for ACPA-negative RA.

Journal ArticleDOI
TL;DR: A multistage vaccination strategy in which the early antigens Ag85B and 6-kDa early secretory antigenic target (ESAT-6) are combined with the latency-associated protein Rv2660c (H56 vaccine), which confers protective immunity characterized by a more efficient containment of late-stage infection.
Abstract: All tuberculosis vaccines currently in clinical trials are designed as prophylactic vaccines based on early expressed antigens. We have developed a multistage vaccination strategy in which the early antigens Ag85B and 6-kDa early secretory antigenic target (ESAT-6) are combined with the latency-associated protein Rv2660c (H56 vaccine). In CB6F1 mice we show that Rv2660c is stably expressed in late stages of infection despite an overall reduced transcription. The H56 vaccine promotes a T cell response against all protein components that is characterized by a high proportion of polyfunctional CD4(+) T cells. In three different pre-exposure mouse models, H56 confers protective immunity characterized by a more efficient containment of late-stage infection than the Ag85B-ESAT6 vaccine (H1) and BCG. In two mouse models of latent tuberculosis, we show that H56 vaccination after exposure is able to control reactivation and significantly lower the bacterial load compared to adjuvant control mice.

Journal ArticleDOI
TL;DR: The recent development of gnotobiotic fish models may be very helpful to study the immune effects of microbiota and probiotics in teleosts, and much more attention has to be paid to the immune mechanisms behind these effects.

Journal ArticleDOI
TL;DR: The results show how IL-12 supplementation by CAR T cells can target otherwise inaccessible tumor lesions, in a manner associated with reduced systemic toxicity, by recruiting and activating innate immune cells for a proinflammatory response.
Abstract: During malignant progression cancer cells tend to lose cell surface expression of MHC and other immune antigens, making them invisible to cytotoxic T cells and therefore inaccessible to tumor antigen-directed immunotherapy. Moreover, cancer cell variants that have lost antigen expression frequently contribute to deadly tumor relapses that occur following treatments that had been initially effective. In an effort to destroy antigen-loss cancer cells in tumors, we created a strategy that combines a chimeric antigen receptor (CAR)-redirected T-cell attack with an engineered local release of the cytokine interleukin 12 (IL-12), which recruits and reinforces macrophage function. Cytotoxic T cells were engineered to release inducible IL-12 upon CAR engagement in the tumor lesion, resulting in destruction of antigen-loss cancer cells that would normally escape. Importantly, elimination of the antigen-loss cancer cells was accompanied by an accumulation of activated macrophages that was critical to the antitumor response, because removing the macrophages abolished the response and restoring them reengaged it. Neutralizing TNF-α also abrogated the elimination of antigen-loss cancer cells, implying this proinflammatory factor in the process. Taken together, our results show how IL-12 supplementation by CAR T cells can target otherwise inaccessible tumor lesions, in a manner associated with reduced systemic toxicity, by recruiting and activating innate immune cells for a proinflammatory response.

Journal ArticleDOI
TL;DR: Characterizing circulating and intratumor PD‐1/PD‐L1 expression and analyzing their association with disease progression in a cohort of hepatitis B virus‐infected patients provides evidence for a new therapeutic target in HCC patients.
Abstract: Programmed death 1 (PD-1) and its ligand (PD-L1) play pivotal roles in regulating host immune responses. However, the inhibitory effects of this pathway on the function of cytotoxic CD8(+) T lymphocytes, the main effector cells in hepatocellular carcinoma (HCC) patients, are not well defined. In this study, we characterized circulating and intratumor PD-1/PD-L1 expression and analyzed their association with disease progression in a cohort of hepatitis B virus-infected patients, including 56 with HCC, 20 with liver cirrhosis (LC) and 20 healthy controls (HC). The frequency of circulating PD-1(+) CD8(+) T cells increased with disease progression from LC to HCC patients versus HC. Furthermore, tumor-infiltrating effector CD8(+) T cells showed a drastic increase in PD-1 expression. These increases in circulating and intratumor PD-1(+) CD8(+) T cells could predict poorer disease progression and postoperative recurrence. Immunohistochemical staining showed that PD-L1 expressing hepatoma cells and apoptotic infiltrating CD8(+) T cells were both enriched in tumor sections. In vitro, CD8(+) T cells induced PD-L1 expression on hepatoma cells in an IFN-γ-dependent manner, which in turn promoted CD8(+) T cells apoptosis, and blocking PD-L1 reversed this effect. Therefore, this study extends our knowledge of the role of the PD-1/PD-L1 pathway in tumor evasion and provides evidence for a new therapeutic target in HCC patients.

Journal ArticleDOI
20 Oct 2011-Blood
TL;DR: The functional significance of the BCR in CLL is discussed, strategies to target B CR signaling as an emerging therapeutic approach are described, and mapping of BCR signaling pathways identifies targets for blockade, aimed to deprive CLL cells of survival and proliferative signals.

Journal ArticleDOI
26 Aug 2011-Immunity
TL;DR: Using a Candida albicans skin infection model, it is shown that direct presentation of antigen by LC is necessary and sufficient for the generation of antigen-specific T helper-17 (Th17) cells but not for thegeneration of cytotoxic lymphocytes (CTLs).

Journal ArticleDOI
16 Mar 2011-Vaccine
TL;DR: AS03's promotion of monocytes as the principal antigen-presenting cells, and its effects on granulocytes and cytokines, may all contribute to enhancing the antigen-specific adaptive immune response.


Journal ArticleDOI
28 Jan 2011-Immunity
TL;DR: It is shown that CD169(+) macrophages phagocytose dead tumor cells transported via lymphatic flow and subsequently crosspresent tumor antigens to CD8(+) T cells to dominate early activation of tumor antigen-specific CD8 (+) T-cells.