scholarly journals P72.06 NLRP4-Mediated Type I Interferon Response Benefits Immune Checkpoint Therapy Through Redirecting CD8+ T Cell Distribution in TME

2021 ◽  
Vol 16 (3) ◽  
pp. S567-S568
Author(s):  
L. Xia ◽  
H. Wang ◽  
H. Dong ◽  
Y. Wang ◽  
S. Lu
Keyword(s):  
T Cell ◽  
Immune Checkpoint ◽  
Type I Interferon ◽  
Cd8 T Cell ◽  
Interferon Response ◽  
Type I ◽  
Cell Distribution

EXTH-77. POLIO VIROTHERAPY OF MURINE BRAIN TUMORS INDUCES MICROGLIA PROLIFERATION AND INFLAMMATION THAT IS POTENTIATED BY IMMUNE CHECKPOINT BLOCKADE

2021 ◽  
Vol 23 (Supplement_6) ◽  
pp. vi181-vi181
Author(s):  
Yuanfan Yang ◽  
Michael Brown ◽  
Kevin Stevenson ◽  
Giselle lopez ◽  
Reb Kornahrens ◽  
...  
Keyword(s):  
T Cell ◽  
Immune Checkpoint ◽  
Response Rate ◽  
Cd8 T Cell ◽  
Gene Set Enrichment Analysis ◽  
Type I ◽  
Acute Type ◽  
Type I Ifn ◽  
Term Survival

Abstract Immunotherapy with polio:rhinovirus recombinant (PVSRIPO) has shown evidence of efficacy in a phase I clinical trial for recurrent GBM, resulting in durable radiographic responses and 21% long-term survival at 36 months. Ongoing research aims to enhance the clinical response rate by resolving the mechanisms of action and therapy resistance in vivo, thereby devising more effective therapies. Mouse glioma (CT2A) cells were intracranially implanted (day 0) in transgenic mice carrying poliovirus receptor CD155, and treated with intratumor PVSRIPO (5×105 pfu; day 6) to dissect early and late events following therapy. A blinded pathological review of 45 post-treatment tumors was performed. On day 8, a histological response, featured by tumor dissociation and shrinkage, with inflammation and microglia enrichment in the treated hemisphere, was common in PVSRIPO group (6/7) compared to controls (0/4). However, the response rate fell over time (7/12 on day 12; 1/7 on day 15) and the therapy was overcome by aggressive tumor regrowth. RNAseq was performed and Gene Set Enrichment Analysis of the tumor microenvironment revealed an acute type-I interferon (IFN)-related inflammation, correlating with the histological findings of profound proinflammatory engagement of microglia (Iba1+) widespread in the treated hemisphere. Microglia proliferation (Ki67+) was observed in the treated hemisphere, likely resulting from PVSRIPO infection, in CT2A and B16 intracranial models. This suggests an association of adaptive antitumor immunity—elicited by immediate intratumor type-I IFN-dominant inflammation—with tumor regression. Thus, buttressing type-I IFN directed antitumor CD8+T cell immunity, e.g. with blockade of the PD1:PD-L1 immune checkpoint, might contribute to tumor remission. Indeed, combination therapy with αPD-L1 antibody in the CT2A model showed longer median survival and higher long-term remission rate compared to monotherapy alone; CD8 T cell depletion can completely abrogate this efficacy with this therapy combination, confirming the role of anti-tumor immunity in this approach.

O032 Timing and magnitude of Type I interferon responses by distinct viral sensors impact CD8 T cell exhaustion and chronic infection

Cytokine ◽  
2012 ◽  
Vol 59 (3) ◽  
pp. 512
Author(s):  
Y. Wang ◽  
M. Swiecki ◽  
M. Cella ◽  
G. Alber ◽  
R.D. Schreiber ◽  
...  
Keyword(s):  
T Cell ◽  
Chronic Infection ◽  
Type I Interferon ◽  
Cd8 T Cell ◽  
Type I ◽  
T Cell Exhaustion ◽  
Cell Exhaustion ◽  
Interferon Responses

scholarly journals Timing and Magnitude of Type I Interferon Responses by Distinct Sensors Impact CD8 T Cell Exhaustion and Chronic Viral Infection

2012 ◽  
Vol 11 (6) ◽  
pp. 631-642 ◽  
Author(s):  
Yaming Wang ◽  
Melissa Swiecki ◽  
Marina Cella ◽  
Gottfried Alber ◽  
Robert D. Schreiber ◽  
...  
Keyword(s):  
T Cell ◽  
Viral Infection ◽  
Type I Interferon ◽  
Cd8 T Cell ◽  
Chronic Viral Infection ◽  
Type I ◽  
T Cell Exhaustion ◽  
Cell Exhaustion ◽  
Interferon Responses

scholarly journals Hypomethylation of STAT1 and HLA-DRB1 is associated with type-I interferon-dependent HLA-DRB1 expression in lupus CD8+ T cells

2018 ◽  
Author(s):  
Shaylynn Miller ◽  
Patrick Coit ◽  
Elizabeth Gensterblum-Miller ◽  
Paul Renauer ◽  
Nathan C Kilian ◽  
...  
Keyword(s):  
Dna Methylation ◽  
T Cells ◽  
T Cell ◽  
Cd8 T Cells ◽  
Type I Interferon ◽  
Interferon Response ◽  
Type I ◽  
Mrna Levels ◽  
Healthy Controls ◽  
Genome Wide

AbstractObjectiveWe examined genome-wide DNA methylation changes in CD8+ T cells from lupus patients and controls, and investigated the functional relevance of some of these changes in lupus.MethodsGenome-wide DNA methylation of lupus and age, sex, and ethnicity-matched control CD8+ T cells was measured using the Infinium MethylationEPIC arrays. Measurement of relevant cell subsets was performed via flow cytometry. Gene expression was quantified by qPCR.ResultsLupus CD8+ T cells had 188 hypomethylated CpG sites compared to healthy matched controls. Among the most hypomethylated were sites associated with HLA-DRB1. Genes involved in the type-I interferon response, including STAT1, were also found to be hypomethylated. IFNα upregulated HLA-DRB1 expression on lupus but not control CD8+ T cells. Lupus and control CD8+ T cells significantly increased STAT1 mRNA levels after treatment with IFNα. The expression of CIITA, a key interferon/STAT1 dependent MHC-class II regulator, is induced by IFNα in lupus CD8+ T cells, but not healthy controls. Co-incubation of naïve CD4+ T cells with IFNα-treated CD8+ T cells led to CD4+ T cell activation, determined by increased expression of CD69, in lupus patients but not in healthy controls. This can be blocked by neutralizing antibodies targeting HLA-DR.ConclusionsLupus CD8+ T cells are epigenetically primed to respond to type-I interferon. We describe an HLA-DRB1+ CD8+ T cell subset that can be induced by IFNα in lupus patients. A possible pathogenic role for CD8+ T cells in lupus that is dependent upon a high type-I interferon environment and epigenetic priming warrants further characterization.

scholarly journals HIV/AIDS Vaccine Candidates Based on Replication-Competent Recombinant Poxvirus NYVAC-C-KC Expressing Trimeric gp140 and Gag-Derived Virus-Like Particles or Lacking the Viral Molecule B19 That Inhibits Type I Interferon Activate Relevant HIV-1-Specific B and T Cell Immune Functions in Nonhuman Primates

2017 ◽  
Vol 91 (9) ◽  
Author(s):  
Juan García-Arriaza ◽  
Beatriz Perdiguero ◽  
Jonathan L. Heeney ◽  
Michael S. Seaman ◽  
David C. Montefiori ◽  
...  
Keyword(s):  
T Cell ◽  
Nonhuman Primates ◽  
Type I Interferon ◽  
Interferon Response ◽  
Type I ◽  
Vaccine Candidates ◽  
Aids Vaccine ◽  
Clade C ◽  
Hiv 1 ◽  
Hiv Aids

ABSTRACT The nonreplicating attenuated poxvirus vector NYVAC expressing clade C(CN54) HIV-1 Env(gp120) and Gag-Pol-Nef antigens (NYVAC-C) showed limited immunogenicity in phase I clinical trials. To enhance the capacity of the NYVAC vector to trigger broad humoral responses and a more balanced activation of CD4+ and CD8+ T cells, here we compared the HIV-1-specific immunogenicity elicited in nonhuman primates immunized with two replicating NYVAC vectors that have been modified by the insertion of the K1L and C7L vaccinia virus host range genes and express the clade C(ZM96) trimeric HIV-1 gp140 protein or a Gag(ZM96)-Pol-Nef(CN54) polyprotein as Gag-derived virus-like particles (termed NYVAC-C-KC). Additionally, one NYVAC-C-KC vector was generated by deleting the viral gene B19R, an inhibitor of the type I interferon response (NYVAC-C-KC-ΔB19R). An immunization protocol mimicking that of the RV144 phase III clinical trial was used. Two groups of macaques received two doses of the corresponding NYVAC-C-KC vectors (weeks 0 and 4) and booster doses with NYVAC-C-KC vectors plus the clade C HIV-1 gp120 protein (weeks 12 and 24). The two replicating NYVAC-C-KC vectors induced enhanced and similar HIV-1-specific CD4+ and CD8+ T cell responses, similar levels of binding IgG antibodies, low levels of IgA antibodies, and high levels of antibody-dependent cellular cytotoxicity responses and HIV-1-neutralizing antibodies. Small differences within the NYVAC-C-KC-ΔB19R group were seen in the magnitude of CD4+ and CD8+ T cells, the induction of some cytokines, and the neutralization of some HIV-1 isolates. Thus, replication-competent NYVAC-C-KC vectors acquired relevant immunological properties as vaccine candidates against HIV/AIDS, and the viral B19 molecule exerts some control of immune functions. IMPORTANCE It is of special importance to find a safe and effective HIV/AIDS vaccine that can induce strong and broad T cell and humoral immune responses correlating with HIV-1 protection. Here we developed novel replicating poxvirus NYVAC-based HIV/AIDS vaccine candidates expressing clade C HIV-1 antigens, with one of them lacking the vaccinia virus B19 protein, an inhibitor of the type I interferon response. Immunization of nonhuman primates with these novel NYVAC-C-KC vectors and the protein component gp120 elicited high levels of T cell and humoral immune responses, with the vector containing a deletion in B19R inducing a trend toward a higher magnitude of CD4+ and CD8+ T cell responses and neutralization of some HIV-1 strains. These poxvirus vectors could be considered HIV/AIDS vaccine candidates based on their activation of potential immune correlates of protection.

scholarly journals Cancer-specific type-I interferon receptor signaling promotes cancer stemness and effector CD8+ T-cell exhaustion

2021 ◽  
Vol 10 (1) ◽  
Author(s):  
Wang Gong ◽  
Christopher R. Donnelly ◽  
Blake R. Heath ◽  
Emily Bellile ◽  
Lorenza A. Donnelly ◽  
...  
Keyword(s):  
T Cell ◽  
Type I Interferon ◽  
Cd8 T Cell ◽  
Type I ◽  
T Cell Exhaustion ◽  
Receptor Signaling ◽  
Cancer Stemness ◽  
Cell Exhaustion ◽  
Interferon Receptor
Sign in / Sign up

Export Citation Format

Share Document