scholarly journals Immunogenic cell death of dendritic cells following modified vaccinia virus Ankara infection enhances CD8+T cell proliferation

2018 ◽  
Vol 48 (12) ◽  
pp. 2042-2054 ◽  
Author(s):  
Kim A. Tappe ◽  
Ramachandramouli Budida ◽  
Metodi V. Stankov ◽  
Theresa Frenz ◽  
Harshit R. Shah ◽  
...  
Keyword(s):  
Cell Proliferation ◽  
Cell Death ◽  
Dendritic Cells ◽  
T Cell ◽  
Vaccinia Virus ◽  
Cd8 T Cell ◽  
T Cell Proliferation ◽  
Immunogenic Cell Death ◽  
Modified Vaccinia Virus Ankara

scholarly journals 782 ALDH1A inhibition as adjuvant to ovarian cancer immunotherapy

2020 ◽  
Vol 8 (Suppl 3) ◽  
pp. A832-A832
Author(s):  
Bingsi Gao ◽  
Mainpal Rana ◽  
Dongli Yang ◽  
Edward Grimley ◽  
Stacy McGonigal ◽  
...  
Keyword(s):  
Ovarian Cancer ◽  
Cell Proliferation ◽  
Cell Death ◽  
T Cell ◽  
Er Stress ◽  
Cancer Cells ◽  
Cell Lines ◽  
T Cell Proliferation ◽  
Immunogenic Cell Death ◽  
Murine Splenocytes

BackgroundDespite some recent advances, new therapeutic approaches for ovarian cancer (OvCa), the 5th leading cause of cancer deaths in women, are clearly needed. Aldehyde dehydrogenase-1A (ALDH1A) enzymes represent a novel therapeutic target for OvCa. ALDH1A is upregulated in OvCa initiating cells and mediate the biosynthesis of retinoic acid (RA) to regulate numerous cellular processes, including proliferation, metastasis, and chemotherapy resistance. We recently identified novel pan-ALDH1A family inhibitors (ALDHi) that induce necroptosis in OvCa stem-like cells and synergize with chemotherapy, leading to tumor eradication in vivo. Here, we hypothesize that, in addition to controlling tumor progression, ALDHi trigger immunogenic cell death (ICD) via necroptosis and can potentiate anti-tumor immunity.MethodsWe performed RNA-Seq on four human OvCa cell lines (A2780, CAOV-3, OVCAR-5, OVSAHO) treated for 8 hours with two different ALDHi. To measure the impact on T cell immunity we performed flow cytometry to measure cell proliferation assays and CD4 naïve differentiation into Th1/Th17/Treg subsets. Molecular targets in the RA pathway were confirmed by western blot.ResultsALDHi triggered significant changes in (i) ER stress unfolded protein response and regulators of the ER stress response, such as ATF4 and EIF2aK3 (PERK), (ii) inflammatory pathways, (iii) cell death, survival, and (iv) gene transcription-RAR signaling. Treatment of cancer cell lines with ALDHi induced expression of Phospho-eIF2α, a marker for the ICD, along with increased expression of ATF3 and ATF4, and calreticulin, suggesting cancer cells undergoing ICD.Using polyclonal stimulation of murine splenocytes and human PBMC, we observed that ALDHi promote T cell proliferation, especially of CD8 T cells. Furthermore, exposure of naïve CD4 cells to Th1 and Treg differentiation conditions leads to increased production of INFγ and reduced number of Foxp3+ iTregs, respectively. Further, in a co-culture of iTreg and stimulated splenocyte, ALDHi treatment diminishes the iTreg’s capacity to induce immune suppression. Ex vivo treatment of ovarian cancer ascites cells with various ALDHi leads to significant decrease of CD14+ cells, an effect associated with downregulation of NR4A1 (NUR77), a nuclear receptor that interacts RAR/RXR, downstream of RA signaling.ConclusionsADLHi induce immunogenic cell death in cancer cells. Immune cells respond to ALDHi in a cell specific manner. ALDHi support CD8 T cell proliferation and CD4 Th1 induction, while inhibiting iTregs. Exposure to ALDHi leads to downregulation of NR4A1 and reduction in suppressive macrophage numbers. Our results support the use of ALDHi as immune modulators in ovarian cancer and adjuvants to immunotherapy.

scholarly journals Inhibition of Allogeneic T Cell Proliferation by Indoleamine 2,3-Dioxygenase–expressing Dendritic Cells

2002 ◽  
Vol 196 (4) ◽  
pp. 447-457 ◽  
Author(s):  
Peter Terness ◽  
Thomas M. Bauer ◽  
Lars Röse ◽  
Christoph Dufter ◽  
Andrea Watzlik ◽  
...  
Keyword(s):  
Cell Proliferation ◽  
T Cells ◽  
Cell Death ◽  
Dendritic Cells ◽  
T Cell ◽  
Antigen Presenting Cells ◽  
T Cell Proliferation ◽  
Inhibition Of Proliferation ◽  
Indoleamine 2,3 Dioxygenase ◽  
Antigen Presenting

Indoleamine 2,3-dioxygenase (IDO), an enzyme involved in the catabolism of tryptophan, is expressed in certain cells and tissues, particularly in antigen-presenting cells of lymphoid organs and in the placenta. It was shown that IDO prevents rejection of the fetus during pregnancy, probably by inhibiting alloreactive T cells, and it was suggested that IDO-expression in antigen-presenting cells may control autoreactive immune responses. Degradation of tryptophan, an essential amino acid required for cell proliferation, was reported to be the mechanism of IDO-induced T cell suppression. Because we wanted to study the action of IDO-expressing dendritic cells (DCs) on allogeneic T cells, the human IDO gene was inserted into an adenoviral vector and expressed in DCs. Transgenic DCs decreased the concentration of tryptophan, increased the concentration of kynurenine, the main tryptophan metabolite, and suppressed allogeneic T cell proliferation in vitro. Kynurenine, 3-hydroxykynurenine, and 3-hydroxyanthranilic acid, but no other IDO-induced tryptophan metabolites, suppressed the T cell response, the suppressive effects being additive. T cells, once stopped in their proliferation, could not be restimulated. Inhibition of proliferation was likely due to T cell death because suppressive tryptophan catabolites exerted a cytotoxic action on CD3+ cells. This action preferentially affected activated T cells and increased gradually with exposure time. In addition to T cells, B and natural killer (NK) cells were also killed, whereas DCs were not affected. Our findings shed light on suppressive mechanisms mediated by DCs and provide an explanation for important biological processes in which IDO activity apparently is increased, such as protection of the fetus from rejection during pregnancy and possibly T cell death in HIV-infected patients.

scholarly journals Immediate-Early Expression of a Recombinant Antigen by Modified Vaccinia Virus Ankara Breaks the Immunodominance of Strong Vector-Specific B8R Antigen in Acute and Memory CD8 T-Cell Responses

2010 ◽  
Vol 84 (17) ◽  
pp. 8743-8752 ◽  
Author(s):  
Karen Baur ◽  
Kay Brinkmann ◽  
Marc Schweneker ◽  
Juliane Pätzold ◽  
Christine Meisinger-Henschel ◽  
...  
Keyword(s):  
T Cell ◽  
Vaccinia Virus ◽  
T Cell Responses ◽  
Cd8 T Cell ◽  
Immediate Early ◽  
Egfp Expression ◽  
Cell Responses ◽  
Modified Vaccinia Virus Ankara ◽  
Memory Cd8 T Cell ◽  
Early Late

ABSTRACT Efficient T-cell responses against recombinant antigens expressed by vaccinia virus vectors require expression of these antigens in the early phase of the virus replication cycle. The kinetics of recombinant gene expression in poxviruses are largely determined by the promoter chosen. We used the highly attenuated modified vaccinia virus Ankara (MVA) to determine the role of promoters in the induction of CD8 T-cell responses. We constructed MVA recombinants expressing either enhanced green fluorescent protein (EGFP) or chicken ovalbumin (OVA), each under the control of a hybrid early-late promoter (pHyb) containing five copies of a strong early element or the well-known early-late p7.5 or pS promoter for comparison. In primary or cultured cells, EGFP expression under the control of pHyb was detected within 30 min, as an immediate-early protein, and remained higher over the first 6 h of infection than p7.5- or pS-driven EGFP expression. Repeated immunizations of mice with recombinant MVA expressing OVA under the control of the pHyb promoter led to superior acute and memory CD8 T-cell responses compared to those to p7.5- and pS-driven OVA. Moreover, OVA expressed under the control of pHyb replaced the MVA-derived B8R protein as the immunodominant CD8 T-cell antigen after three or more immunizations. This is the first demonstration of an immediate-early neoantigen expressed by a poxviral vector resulting in superior induction of neoantigen-specific CD8 T-cell responses.

scholarly journals Myeloid Dendritic Cells from Human Cutaneous Squamous Cell Carcinoma Are Poor Stimulators of T-Cell Proliferation

2009 ◽  
Vol 129 (10) ◽  
pp. 2451-2462 ◽  
Author(s):  
Mark J. Bluth ◽  
Lisa C. Zaba ◽  
Dariush Moussai ◽  
Mayte Suárez-Fariñas ◽  
Helen Kaporis ◽  
...  
Keyword(s):  
Cell Proliferation ◽  
Squamous Cell Carcinoma ◽  
Dendritic Cells ◽  
T Cell ◽  
Cell Carcinoma ◽  
Squamous Cell ◽  
Cutaneous Squamous Cell Carcinoma ◽  
T Cell Proliferation ◽  
Myeloid Dendritic Cells

scholarly journals Novel Recombinant Mycobacterium bovis BCG, Ovine Atadenovirus, and Modified Vaccinia Virus Ankara Vaccines Combine To Induce Robust Human Immunodeficiency Virus-Specific CD4 and CD8 T-Cell Responses in Rhesus Macaques

2010 ◽  
Vol 84 (12) ◽  
pp. 5898-5908 ◽  
Author(s):  
Maximillian Rosario ◽  
Richard Hopkins ◽  
John Fulkerson ◽  
Nicola Borthwick ◽  
Máire F. Quigley ◽  
...  
Keyword(s):  
T Cell ◽  
Vaccinia Virus ◽  
Mycobacterium Bovis ◽  
Ex Vivo ◽  
Rhesus Macaques ◽  
T Cell Responses ◽  
Cd8 T Cell ◽  
Cell Responses ◽  
Modified Vaccinia Virus Ankara ◽  
Hiv 1

ABSTRACT Mycobacterium bovis bacillus Calmette-Guérin (BCG), which elicits a degree of protective immunity against tuberculosis, is the most widely used vaccine in the world. Due to its persistence and immunogenicity, BCG has been proposed as a vector for vaccines against other infections, including HIV-1. BCG has a very good safety record, although it can cause disseminated disease in immunocompromised individuals. Here, we constructed a recombinant BCG vector expressing HIV-1 clade A-derived immunogen HIVA using the recently described safer and more immunogenic BCG strain AERAS-401 as the parental mycobacterium. Using routine ex vivo T-cell assays, BCG.HIVA401 as a stand-alone vaccine induced undetectable and weak CD8 T-cell responses in BALB/c mice and rhesus macaques, respectively. However, when BCG.HIVA401 was used as a priming component in heterologous vaccination regimens together with recombinant modified vaccinia virus Ankara-vectored MVA.HIVA and ovine atadenovirus-vectored OAdV.HIVA vaccines, robust HIV-1-specific T-cell responses were elicited. These high-frequency T-cell responses were broadly directed and capable of proliferation in response to recall antigen. Furthermore, multiple antigen-specific T-cell clonotypes were efficiently recruited into the memory pool. These desirable features are thought to be associated with good control of HIV-1 infection. In addition, strong and persistent T-cell responses specific for the BCG-derived purified protein derivative (PPD) antigen were induced. This work is the first demonstration of immunogenicity for two novel vaccine vectors and the corresponding candidate HIV-1 vaccines BCG.HIVA401 and OAdV.HIVA in nonhuman primates. These results strongly support their further exploration.

Flow cytometric analysis of T cell proliferation in a mixed lymphocyte reaction with dendritic cells

2003 ◽  
Vol 275 (1-2) ◽  
pp. 57-68 ◽  
Author(s):  
Xuan Duc Nguyen ◽  
Hermann Eichler ◽  
Alex Dugrillon ◽  
Christoph Piechaczek ◽  
Michael Braun ◽  
...  
Keyword(s):  
Cell Proliferation ◽  
Dendritic Cells ◽  
T Cell ◽  
Mixed Lymphocyte Reaction ◽  
Flow Cytometric Analysis ◽  
T Cell Proliferation ◽  
Flow Cytometric
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