共查询到20条相似文献,搜索用时 218 毫秒
1.
Nikolaj Pagh Kristensen Christina Heeke Siri A. Tvingsholm Annie Borch Arianna Draghi Michael D. Crowther Ibel Carri Kamilla K. Munk Jeppe Sejer Holm Anne-Mette Bjerregaard Amalie Kai Bentzen Andrea M. Marquard Zoltan Szallasi Nicholas McGranahan Rikke Andersen Morten Nielsen Gran B. Jnsson Marco Donia Inge Marie Svane Sine Reker Hadrup 《The Journal of clinical investigation》2022,132(2)
2.
A J Robert McGray Robin Hallett Dannie Bernard Stephanie L Swift Ziqiang Zhu Florentina Teoderascu Heather VanSeggelen John A Hassell Arthur A Hurwitz Yonghong Wan Jonathan L Bramson 《Molecular therapy》2014,22(1):206-218
Despite clear evidence of immunogenicity, cancer vaccines only provide a modest clinical benefit. To evaluate the mechanisms that limit tumor regression following vaccination, we have investigated the weak efficacy of a highly immunogenic experimental vaccine using a murine melanoma model. We discovered that the tumor adapts rapidly to the immune attack instigated by tumor-specific CD8+ T cells in the first few days following vaccination, resulting in the upregulation of a complex set of biological networks, including multiple immunosuppressive processes. This rapid adaptation acts to prevent sustained local immune attack, despite continued infiltration by increasing numbers of tumor-specific T cells. Combining vaccination with adoptive transfer of tumor-specific T cells produced complete regression of the treated tumors but did not prevent the adaptive immunosuppression. In fact, the adaptive immunosuppressive pathways were more highly induced in regressing tumors, commensurate with the enhanced level of immune attack. Examination of tumor infiltrating T-cell functionality revealed that the adaptive immunosuppression leads to a progressive loss in T-cell function, even in tumors that are regressing. These novel observations that T cells produced by therapeutic intervention can instigate a rapid adaptive immunosuppressive response within the tumor have important implications for clinical implementation of immunotherapies. 相似文献
3.
Kenneth Hung Robert Hayashi Anne Lafond-Walker Charles Lowenstein Drew Pardoll Hyam Levitsky 《The Journal of experimental medicine》1998,188(12):2357-2368
The induction of optimal systemic antitumor immunity involves the priming of both CD4+ and CD8+ T cells specific for tumor-associated antigens. The role of CD4+ T helper cells (Th) in this response has been largely attributed to providing regulatory signals required for the priming of major histocompatibility complex class I restricted CD8+ cytolytic T lymphocytes, which are thought to serve as the dominant effector cell mediating tumor killing. However, analysis of the effector phase of tumor rejection induced by vaccination with irradiated tumor cells transduced to secrete granulocyte/macrophage colony-stimulating factor indicates a far broader role for CD4+ T cells in orchestrating the host response to tumor. This form of immunization leads to the simultaneous induction of Th1 and Th2 responses, both of which are required for maximal systemic antitumor immunity. Cytokines produced by these CD4+ T cells activate eosinophils as well as macrophages that produce both superoxide and nitric oxide. Both of these cell types then collaborate within the site of tumor challenge to cause its destruction. 相似文献
4.
Ferry Ossendorp Erica Mengedé Marcel Camps Rian Filius Cornelis J.M. Melief 《The Journal of experimental medicine》1998,187(5):693-702
This study shows that induction of tumor-specific CD4+ T cells by vaccination with a specific viral T helper epitope, contained within a synthetic peptide, results in protective immunity against major histocompatibility complex (MHC) class II negative, virus-induced tumor cells. Protection was also induced against sarcoma induction by acutely transforming retrovirus. In contrast, no protective immunity was induced by vaccination with an unrelated T helper epitope. By cytokine pattern analysis, the induced CD4+ T cells were of the T helper cell 1 type. The peptide-specific CD4+ T cells did not directly recognize the tumor cells, indicating involvement of cross-priming by tumor-associated antigen-presenting cells. The main effector cells responsible for tumor eradication were identified as CD8+ cytotoxic T cells that were found to recognize a recently described immunodominant viral gag-encoded cytotoxic T lymphocyte (CTL) epitope, which is unrelated to the viral env-encoded T helper peptide sequence. Simultaneous vaccination with the tumor-specific T helper and CTL epitopes resulted in strong synergistic protection. These results indicate the crucial role of T helper cells for optimal induction of protective immunity against MHC class II negative tumor cells. Protection is dependent on tumor-specific CTLs in this model system and requires cross-priming of tumor antigens by specialized antigen-presenting cells. Thus, tumor-specific T helper epitopes have to be included in the design of epitope-based vaccines.Adequate T helper cell activation is essential in the initiation of an immune reaction. The inability to control tumor outgrowth can be due to inadequate T helper responses underlying poor tumor-specific immunity. In the cellular immune response, specialized APCs process protein and present antigenic peptide fragments in MHC class II molecules to CD4+ T helper lymphocytes. These provide “help” to effector cells via the production of cytokines. Although tumor cells can directly present endogenously processed antigenic peptide in surface MHC class I molecules to CD8+ CTL precursors, initiation of tumor-specific CTL responses is likely to involve indirect presentation of tumor antigens by specialized APCs.Evidence for a role of T helper cell–mediated immunity comes from studies with genetically modified tumor cells. CD4+ cells can be directly activated by transfection of MHC class II α and β chain genes in mouse tumor cells (1–4). These cells become immunogenic, lose their tumorigenicity, and even induce protection against wild-type MHC class II negative tumors, indicating that direct MHC class II presentation of tumor expressed antigens can induce efficient anti–tumor responses.A central role of CD4+ T cells emerged from studies of immunity against FMR (Friend, Moloney, Rauscher)1 murine leukemia virus (MuLV) type tumors by Greenberg (5). Transfer of purified polyclonal T cells from FBL (Friend MuLV-induced erythroleukemia cell line) vaccinated mice in naive animals can protect these mice against subsequent tumor challenge. Both purified CD4+ and CD8+ T cells transfer protection to FBL tumors (6). FBL cells do not express MHC class II molecules, but CD4+ T cells can protect mice even in the absence of CD8+ T cells. In this case, macrophages seem to play an important effector role. CD8+ T cells can only be effective if CD4+ T cells are present or if exogenous IL-2 is administered. Neither B cells nor NK cells seem to exert a significant role in the FBL sytem. These data suggest involvement of APCs, presenting tumor antigens, and a crucial regulatory role of Ths, which was strongly supported by experiments performed in Friend MuLV env-transgenic mice (7). These mice were rendered tolerant for env-specific Th responses and it was not possible to protect these mice against FBL tumors by vaccination.Immune responsiveness to MuLV is classically regulated by the genes of the H-2 (MHC) complex (8). In particular, the H-2b haplotype confers resistance, and studies using H-2 recombinant and H-2 mutant mouse strains have mapped the protective effects to the class II I-Ab locus (9, 10). This MHC class II association indicates an important role of T helper cells influencing both CTL activity as well as class switching of antiviral antibodies from IgM to IgG. The H-2 I-Ab phenotype protects against early lymphomagenesis. The identification of two Friend MuLV env-derived epitopes, presented by MHC class II, I-Ab and I-Eb/d, respectively, indicated that tumor-directed T helper immunity is virus specific (11). The few lymphomas that arise in H-2b mice have abrogated viral antigen or (more rarely) MHC class I expression (12), indicating that CTLs also play a crucial role. CTLs have been proven to recognize viral antigens, both gag and env proteins encode CTL epitopes (13). We have identified a Kb-presented, env-derived Moloney and Rauscher CTL epitope that is subdominant in C57BL/6 mice making use of the Db mutant BM13 mouse strain (14). The Db-presented gag-leader (gag-L) derived immunodominant CTL epitope for the FMR type of MuLV has been identified only recently (15).Vaccination with a synthetic peptide comprising a relevant T cell epitope is a powerful method to induce highly specific T cells. Protective vaccination using CTL peptide epitopes has been achieved in pathogenic viral models (16, 17) and tumor models (18–20). Peptide vaccination in IFA led to measurable specific CTL induction and protective immunity against virulent virus or tumor cells. Importantly, peptide vaccination can also be applied succesfully for therapy of established tumors by presenting the peptide in IFA, on RMA-S cells, or on activated dendritic cells (21, 22).We now report the induction of tumor-protective immunity by a single vaccination with a tumor-specific MuLV env-encoded T helper peptide. Strong protection can be achieved against highly aggressive tumor cells that lack MHC class II expression. This indicates the requirement of cross-priming of tumor antigens by local APCs. We show that CD8+ T cells, recognizing the gag-L–encoded CTL epitope, are crucial effector cells that are efficiently activated with help from peptide-primed tumor-specific CD4+ T cells. Vaccination with a mixture of the T helper peptide and the immunodominant CTL epitope resulted in synergistic, long-term tumor protection. 相似文献
5.
Tumors are theoretically capable of eliciting an antitumor immune response, but are often poorly immunogenic. Oncolytic viruses (OVs) have recently emerged as a promising strategy for the immunogenic delivery of tumor-associated antigens (TAAs) to cancer patients. However, safe and effective OV/TAA therapies have not yet been established. We have previously demonstrated that vectors based on Sindbis virus (SV) can inhibit tumor growth and activate the innate immune system in mice. Here, we demonstrate that SV vectors carrying a TAA generate a dramatically enhanced therapeutic effect in mice bearing subcutaneous, intraperitoneal, and lung cancers. Notably, SV/TAA efficacy was not dependent on tumor cell targeting, but was characterized by the transient expression of TAAs in lymph nodes draining the injection site. Early T-cell activation at this site was followed by a robust influx of NKG2D expressing antigen-specific cytotoxic CD8+ T cells into the tumor site, subsequently leading to the generation of long-lasting memory T cells which conferred protection against rechallenge with TAA-positive as well as TAA-negative tumor cells. By combining in vivo imaging, flow cytometry, cytotoxicity/cytokine assays, and tetramer analysis, we investigated the relationship between these events and propose a model for CD8+ T-cell activation during SV/TAA therapy. 相似文献
6.
7.
Rebekka Duhen Olivier Fesneau Kimberly A. Samson Alexandra K. Frye Michael Beymer Venkatesh Rajamanickam David Ross Eric Tran Brady Bernard Andrew D. Weinberg Thomas Duhen 《The Journal of clinical investigation》2022,132(12)
CD4+ Th cells play a key role in orchestrating immune responses, but the identity of the CD4+ Th cells involved in the antitumor immune response remains to be defined. We analyzed the immune cell infiltrates of head and neck squamous cell carcinoma and colorectal cancers and identified a subset of CD4+ Th cells distinct from FOXP3+ Tregs that coexpressed programmed cell death 1 (PD-1) and ICOS. These tumor-infiltrating lymphocyte CD4+ Th cells (CD4+ Th TILs) had a tissue-resident memory phenotype, were present in MHC class II–rich areas, and proliferated in the tumor, suggesting local antigen recognition. The T cell receptor repertoire of the PD-1+ICOS+ CD4+ Th TILs was oligoclonal, with T cell clones expanded in the tumor, but present at low frequencies in the periphery. Finally, these PD-1+ICOS+ CD4+ Th TILs were shown to recognize both tumor-associated antigens and tumor-specific neoantigens. Our findings provide an approach for isolating tumor-reactive CD4+ Th TILs directly ex vivo that will help define their role in the antitumor immune response and potentially improve future adoptive T cell therapy approaches. 相似文献
8.
9.
Jingying Zhou Allen K.L. Cheung Zhiwu Tan Haibo Wang Wenbo Yu Yanhua Du Yuanxi Kang Xiaofan Lu Li Liu Kwok-Yung Yuen Zhiwei Chen 《The Journal of clinical investigation》2013,123(6):2629-2642
Viral vector–based vaccines that induce protective CD8+ T cell immunity can prevent or control pathogenic SIV infections, but issues of preexisting immunity and safety have impeded their implementation in HIV-1. Here, we report the development of what we believe to be a novel antigen-targeting DNA vaccine strategy that exploits the binding of programmed death-1 (PD1) to its ligands expressed on dendritic cells (DCs) by fusing soluble PD1 with HIV-1 GAG p24 antigen. As compared with non–DC-targeting vaccines, intramuscular immunization via electroporation (EP) of the fusion DNA in mice elicited consistently high frequencies of GAG-specific, broadly reactive, polyfunctional, long-lived, and cytotoxic CD8+ T cells and robust anti-GAG antibody titers. Vaccination conferred remarkable protection against mucosal challenge with vaccinia GAG viruses. Soluble PD1–based vaccination potentiated CD8+ T cell responses by enhancing antigen binding and uptake in DCs and activation in the draining lymph node. It also increased IL-12–producing DCs and engaged antigen cross-presentation when compared with anti-DEC205 antibody-mediated DC targeting. The high frequency of durable and protective GAG-specific CD8+ T cell immunity induced by soluble PD1–based vaccination suggests that PD1-based DNA vaccines could potentially be used against HIV-1 and other pathogens. 相似文献
10.
Nina Chi Sabins Jennifer L Taylor Kellsye PL Fabian Leonard J Appleman Jodi K Maranchie Donna Beer Stolz Walter J Storkus 《Molecular therapy》2013,21(10):1958-1968
Tumor blood vessels are frequently inefficient in their design and function, leading to high interstitial fluid pressure, hypoxia, and acidosis in the tumor microenvironment (TME), rendering tumors refractory to the delivery of chemotherapeutic agents and immune effector cells. Here we identified the NOTCH antagonist delta-like 1 homologue (DLK1) as a vascular pericyte-associated antigen expressed in renal cell carcinomas (RCC), but not in normal kidney tissues in mice and humans. Vaccination of mice bearing established RCC against DLK1 led to immune-mediated elimination of DLK1+ pericytes and to blood vessel normalization (i.e., decreased vascular permeability and intratumoral hypoxia) in the TME, in association with tumor growth suppression. After therapeutic vaccination, tumors displayed increased prevalence of activated VCAM1+CD31+ vascular endothelial cells (VECs) and CXCL10, a type-1 T cell recruiting chemokine, in concert with increased levels of type-1 CD8+ tumor-infiltrating lymphocytes (TIL). Vaccination against DLK1 also yielded (i) dramatic reductions in Jarid1B+, CD133+, and CD44+ (hypoxia-responsive) stromal cell populations, (ii) enhanced tumor cell apoptosis, and (iii) increased NOTCH signaling in the TME. Coadministration of a γ-secretase inhibitor (N-[N-(3,5-Difluorophenacetyl-l-alanyl)]-(S)-phenylglycine t-butyl ester (DAPT)) that interferes with canonical NOTCH signaling resulted in the partial loss of therapeutic benefits associated with lentivirus encoding full-length murine (lvDLK1)-based vaccination. 相似文献
11.
Elodie Picarda Séverine Bézie Vanessa Venturi Klara Echasserieau Emmanuel Mérieau Aurélie Delhumeau Karine Renaudin Sophie Brouard Karine Bernardeau Ignacio Anegon Carole Guillonneau 《The Journal of clinical investigation》2014,124(6):2497-2512
In a rat heart allograft model, preventing T cell costimulation with CD40Ig leads to indefinite allograft survival, which is mediated by the induction of CD8+CD45RClo regulatory T cells (CD8+CD40Ig Tregs) interacting with plasmacytoid dendritic cells (pDCs). The role of TCR-MHC-peptide interaction in regulating Treg activity remains a topic of debate. Here, we identified a donor MHC class II–derived peptide (Du51) that is recognized by TCR-biased CD8+CD40Ig Tregs and activating CD8+CD40Ig Tregs in both its phenotype and suppression of antidonor alloreactive T cell responses. We generated a labeled tetramer (MHC-I RT1.Aa/Du51) to localize and quantify Du51-specific T cells within rat cardiac allografts and spleen. RT1.Aa/Du51-specific CD8+CD40Ig Tregs were the most suppressive subset of the total Treg population, were essential for in vivo tolerance induction, and expressed a biased, restricted Vβ11-TCR repertoire in the spleen and the graft. Finally, we demonstrated that treatment of transplant recipients with the Du51 peptide resulted in indefinite prolongation of allograft survival. These results show that CD8+CD40Ig Tregs recognize a dominant donor antigen, resulting in TCR repertoire alterations in the graft and periphery. Furthermore, this allopeptide has strong therapeutic activity and highlights the importance of TCR-peptide-MHC interaction for Treg generation and function. 相似文献
12.
Mads Hald Andersen Rikke Bk Srensen Marie K. Brimnes Inge Marie Svane Jürgen C. Becker Per thor Straten 《The Journal of clinical investigation》2009,119(8):2245-2256
Treg deficiencies are associated with autoimmunity. Conversely, CD4+ and CD8+ Tregs accumulate in the tumor microenvironment and are associated with prevention of antitumor immunity and anticancer immunotherapy. Recently, CD4+ Tregs have been much studied, but little is known about CD8+ Tregs and the antigens they recognize. Here, we describe what we believe to be the first natural target for CD8+ Tregs. Naturally occurring HLA-A2–restricted CD8+ T cells specific for the antiinflammatory molecule heme oxygenase-1 (HO-1) were able to suppress cellular immune responses with outstanding efficacy. HO-1–specific CD8+ T cells were detected ex vivo and in situ among T cells from cancer patients. HO-1–specific T cells isolated from the peripheral blood of cancer patients inhibited cytokine release, proliferation, and cytotoxicity of other immune cells. Notably, the inhibitory effect of HO-1–specific T cells was far more pronounced than that of conventional CD4+CD25+CD127– Tregs. The inhibitory activity of HO-1–specific T cells seemed at least partly to be mediated by soluble factors. Our data link the cellular stress response to the regulation of adaptive immunity, expand the role of HO-1 in T cell–mediated immunoregulation, and establish a role for peptide-specific CD8+ T cells in regulating cellular immune responses. Identification of potent antigen-specific CD8+ Tregs may open new avenues for therapeutic interventions in both autoimmune diseases and cancer. 相似文献
13.
Daniel J Hui Etiena Basner-Tschakarjan Yifeng Chen Robert J Davidson George Buchlis Mustafa Yazicioglu Gary C Pien Jonathan D Finn Virginia Haurigot Alex Tai David W Scott Leslie P Cousens Shangzhen Zhou Anne S De Groot Federico Mingozzi 《Molecular therapy》2013,21(9):1727-1737
Immune responses directed against viral capsid proteins constitute a main safety concern in the use of adeno-associated virus (AAV) as gene transfer vectors in humans. Pharmacological immunosuppression has been proposed as a solution to the problem; however, the approach suffers from several potential limitations. Using MHC class II epitopes initially identified within human IgG, named Tregitopes, we showed that it is possible to modulate CD8+ T cell responses to several viral antigens in vitro. We showed that incubation of peripheral blood mononuclear cells with these epitopes triggers proliferation of CD4+CD25+FoxP3+ T cells that suppress killing of target cells loaded with MHC class I antigens in an antigen-specific fashion, through a mechanism that seems to require cell-to-cell contact. Expression of a construct encoding for the AAV capsid structural protein fused to Tregitopes resulted in reduction of CD8+ T cell reactivity against the AAV capsid following immunization with an adenoviral vector expressing capsid. This was accompanied by an increase in frequency of CD4+CD25+FoxP3+ T cells in spleens and lower levels of inflammatory infiltrates in injected tissues. This proof-of-concept study demonstrates modulation of CD8+ T cell reactivity to an antigen using regulatory T cell epitopes is possible. 相似文献
14.
Dayson Moreira Sagus Sampath Haejung Won Seok Voon White Yu-Lin Su Marice Alcantara Chongkai Wang Peter Lee Ellie Maghami Erminia Massarelli Marcin Kortylewski 《The Journal of clinical investigation》2021,131(2)
The tumor microenvironment affects the outcome of radiotherapy against head and neck squamous cell carcinoma (HNSCC). We recently found that tolerogenic myeloid cells accumulate in the circulation of HNSCC patients undergoing radiotherapy. Here, we analyzed tumor-containing lymph node biopsies collected from these patients. After 2 weeks of radiotherapy, we found an increase in tumor-associated macrophages (TAMs) with activated STAT3, while CD8+ T cells were reduced as detected using multiplex IHC. Gene expression profiling indicated upregulation of M2 macrophage–related genes (CD163, CD206), immunosuppressive mediators (ARG1, LIF, TGFB1), and Th2 cytokines (IL4, IL5) in irradiated tumors. We next validated STAT3 as a potential target in human HNSCC-associated TAMs, using UM-SCC1 xenotransplants in humanized mice. Local injections of myeloid cell–targeted STAT3 antisense oligonucleotide (CpG-STAT3ASO) activated human DCs/macrophages and promoted CD8+ T cell recruitment, thereby arresting UM-SCC1 tumor growth. Furthermore, CpG-STAT3ASO synergized with tumor irradiation against syngeneic HPV+ mEERL and HPV– MOC2 HNSCC tumors in mice, triggering tumor regression and/or extending animal survival. The antitumor immune responses were CD8+ and CD4+ T cell dependent and associated with the activation of antigen-presenting cells (DCs/M1 macrophages) and increased CD8+ to regulatory T cell ratio. Our observations suggest that targeted inhibition of STAT3 in tumor-associated myeloid cells augments the efficacy of radiotherapy against HNSCC. 相似文献
15.
David M. Lewinsohn Mark R. Alderson Andria L. Briden Stanley R. Riddell Steven G. Reed Kenneth H. Grabstein 《The Journal of experimental medicine》1998,187(10):1633-1640
Previous studies in murine models, including those using the β2 microglobulin knockout mouse, have suggested an important role for CD8+ T cells in host defense to Mycobacterium tuberculosis (Mtb). At present, little is understood about these cells in the human immune response to tuberculosis. This report demonstrates the existence of human Mtb-reactive CD8+ T cells. These cells are present preferentially in persons infected with Mtb and produce interferon γ in response to stimulation with Mtb-infected target cells. Recognition of Mtb-infected cells by these CD8+ T cells is restricted neither by the major histocompatibility complex (MHC) class I A, B, or C alleles nor by CD1, although it is inhibited by anti–MHC class I antibody. The Mtb-specific CD8+ T cells recognize an antigen which is generated in the proteasome, but which does not require transport through the Golgi-ER. The data suggest the possible use of nonpolymorphic MHC class Ib antigen presenting structures other than CD1. 相似文献
16.
Kevin J Curran Beatrijs A Seinstra Yan Nikhamin Raymond Yeh Yelena Usachenko Dayenne G van Leeuwen Terence Purdon Hollie J Pegram Renier J Brentjens 《Molecular therapy》2015,23(4):769-778
Adoptive cell therapy with genetically modified T cells expressing a chimeric antigen receptor (CAR) is a promising therapy for patients with B-cell acute lymphoblastic leukemia. However, CAR-modified T cells (CAR T cells) have mostly failed in patients with solid tumors or low-grade B-cell malignancies including chronic lymphocytic leukemia with bulky lymph node involvement. Herein, we enhance the antitumor efficacy of CAR T cells through the constitutive expression of CD40 ligand (CD40L, CD154). T cells genetically modified to constitutively express CD40L (CD40L-modified T cells) demonstrated increased proliferation and secretion of proinflammatory TH1 cytokines. Further, CD40L-modified T cells augmented the immunogenicity of CD40+ tumor cells by the upregulated surface expression of costimulatory molecules (CD80 and CD86), adhesion molecules (CD54, CD58, and CD70), human leukocyte antigen (HLA) molecules (Class I and HLA-DR), and the Fas-death receptor (CD95). Additionally, CD40L-modified T cells induced maturation and secretion of the proinflammatory cytokine interleukin-12 by monocyte-derived dendritic cells. Finally, tumor-targeted CD19-specific CAR/CD40L T cells exhibited increased cytotoxicity against CD40+ tumors and extended the survival of tumor-bearing mice in a xenotransplant model of CD19+ systemic lymphoma. This preclinical data supports the clinical application of CAR T cells additionally modified to constitutively express CD40L with anticipated enhanced antitumor efficacy. 相似文献
17.
18.
Laurent Derré Jean-Paul Rivals Camilla Jandus Sonia Pastor Donata Rimoldi Pedro Romero Olivier Michielin Daniel Olive Daniel E. Speiser 《The Journal of clinical investigation》2010,120(1):157-167
The function of antigen-specific CD8+ T cells, which may protect against
both infectious and malignant diseases, can be impaired by ligation of their
inhibitory receptors, which include CTL-associated protein 4 (CTLA-4) and programmed
cell death 1 (PD-1). Recently, B and T lymphocyte attenuator (BTLA) was identified as
a novel inhibitory receptor with structural and functional similarities to CTLA-4 and
PD-1. BTLA triggering leads to decreased antimicrobial and autoimmune T cell
responses in mice, but its functions in humans are largely unknown. Here we have
demonstrated that as human viral antigen–specific CD8+ T cells
differentiated from naive to effector cells, their surface expression of BTLA was
gradually downregulated. In marked contrast, human melanoma tumor
antigen–specific effector CD8+ T cells persistently expressed
high levels of BTLA in vivo and remained susceptible to functional inhibition by its
ligand herpes virus entry mediator (HVEM). Such persistence of BTLA expression was
also found in tumor antigen–specific CD8+ T cells from
melanoma patients with spontaneous antitumor immune responses and after conventional
peptide vaccination. Remarkably, addition of CpG oligodeoxynucleotides to the vaccine
formulation led to progressive downregulation of BTLA in vivo and consequent
resistance to BTLA-HVEM–mediated inhibition. Thus, BTLA activation
inhibits the function of human CD8+ cancer-specific T cells, and
appropriate immunotherapy may partially overcome this inhibition. 相似文献
19.
Uncovering a novel role of PLCβ4 in selectively mediating TCR signaling in CD8+ but not CD4+ T cells
Miwa Sasai Ji Su Ma Masaaki Okamoto Kohei Nishino Hikaru Nagaoka Eizo Takashima Ariel Pradipta Youngae Lee Hidetaka Kosako Pann-Ghill Suh Masahiro Yamamoto 《The Journal of experimental medicine》2021,218(7)
Because of their common signaling molecules, the main T cell receptor (TCR) signaling cascades in CD4+ and CD8+ T cells are considered qualitatively identical. Herein, we show that TCR signaling in CD8+ T cells is qualitatively different from that in CD4+ T cells, since CD8α ignites another cardinal signaling cascade involving phospholipase C β4 (PLCβ4). TCR-mediated responses were severely impaired in PLCβ4-deficient CD8+ T cells, whereas those in CD4+ T cells were intact. PLCβ4-deficient CD8+ T cells showed perturbed activation of peripheral TCR signaling pathways downstream of IP3 generation. Binding of PLCβ4 to the cytoplasmic tail of CD8α was important for CD8+ T cell activation. Furthermore, GNAQ interacted with PLCβ4, mediated double phosphorylation on threonine 886 and serine 890 positions of PLCβ4, and activated CD8+ T cells in a PLCβ4-dependent fashion. PLCβ4-deficient mice exhibited defective antiparasitic host defense and antitumor immune responses. Altogether, PLCβ4 differentiates TCR signaling in CD4+ and CD8+ T cells and selectively promotes CD8+ T cell–dependent adaptive immunity. 相似文献
20.
John G. Facciponte Stefano Ugel Francesco De Sanctis Chunsheng Li Liping Wang Gautham Nair Sandy Sehgal Arjun Raj Efthymia Matthaiou George Coukos Andrea Facciabene 《The Journal of clinical investigation》2014,124(4):1497-1511
Tumor endothelial marker 1 (TEM1; also known as endosialin or CD248) is a protein found on tumor vasculature and in tumor stroma. Here, we tested whether TEM1 has potential as a therapeutic target for cancer immunotherapy by immunizing immunocompetent mice with Tem1 cDNA fused to the minimal domain of the C fragment of tetanus toxoid (referred to herein as Tem1-TT vaccine). Tem1-TT vaccination elicited CD8+ and/or CD4+ T cell responses against immunodominant TEM1 protein sequences. Prophylactic immunization of animals with Tem1-TT prevented or delayed tumor formation in several murine tumor models. Therapeutic vaccination of tumor-bearing mice reduced tumor vascularity, increased infiltration of CD3+ T cells into the tumor, and controlled progression of established tumors. Tem1-TT vaccination also elicited CD8+ cytotoxic T cell responses against murine tumor-specific antigens. Effective Tem1-TT vaccination did not affect angiogenesis-dependent physiological processes, including wound healing and reproduction. Based on these data and the widespread expression of TEM1 on the vasculature of different tumor types, we conclude that targeting TEM1 has therapeutic potential in cancer immunotherapy. 相似文献