EXTH-61. MODULATION OF THE IL-27 RECEPTOR SIGNALING PATHWAY IN GLIOBLASTOMA AND ONCOLYTIC VIROTHERAPY

2021 ◽  
Vol 23 (Supplement_6) ◽  
pp. vi177-vi177
Author(s):  
Eleni Panagioti ◽  
Michal Nowicki ◽  
William Goins ◽  
Jorge Jimenez Macias ◽  
Julia Escobar ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Signaling Pathway ◽  
Glioma Cells ◽  
Oncolytic Virotherapy ◽  
Receptor Signaling ◽  
Inhibitory Receptors ◽  
Receptor Signaling Pathway ◽  
Hsv 1

Abstract Glioblastoma (GBM) is the most common primary malignant brain tumor in adults with median overall survival of 14-16 months. Glioblastoma progression involves multiple immunosuppressive pathways hindering the success of cancer immunotherapy. Oncolytic virotherapy is a promising approach to reprogram the glioblastoma microenvironment and restore anti-tumor immunity. Interleukin (IL)-27 receptor signaling pathway regulates development of effector T cells, IL-10 producing T regulatory type 1 (Tr1) cells and induction of co-inhibitory receptors associated with T cell exhaustion in cancer. In this study, we sought to tackle local and systemic GBM-induced immunosuppression using the novel rQNestin34.5v2 oncolytic herpes simplex virus type-1 (HSV-1), engineered to selectively replicate in glioma cells together with genetic disruptions of the IL-27 receptor signaling pathway. The antitumor activity of HSV-1 rQNestin34.5v2 was evaluated in IL-27ra-/- and wild-type C57BL/6 mice harboring orthotopic CT-2A and GL261 glioblastoma and in athymic nude mice harboring orthotopic patient derived glioblastoma xenografts (PDXs) selected from patients that had been treated in a clinical trial of intratumoral administration of HSV-1 rQNestin34.5v2 (ClinicalTrials.gov: NCT03152318). HSV-1 rQNestin34.5v2 exhibited superior capacity to infect glioma cells in vitro triggering release of proinflammatory cytokines and inducing immunogenic cell death in infected cells. Immune phenotyping of GL261 and CT-2A gliomas revealed astrocytes and microglia express the highest levels of IL-27R. Lack of IL-27R signaling decreased expression of the co-inhibitory receptors PD-1 and Tim-3 on circulating CD4+ T cells suggesting altered CD4+ T cell responses. In the tumor microenvironment, lack of IL-27R signaling decreased immune suppression as evidenced by reduced interleukin (IL)-10 secretion by glioma cells. Despite positive functional modifications on CD4+ T cells, global lack of IL-27R signaling promoted tumor growth accompanied by increased circulating myeloid derived suppressor cells (MDSCs) in the GL261 model. Experiments to address the immunoregulatory role of IL-27R signaling during HSV-1 rQNestin34.5v2 virotherapy-induced glioma tissue destruction are ongoing.

scholarly journals T cell receptor signaling pathway is overexpressed in CD4+ T cells from HAM/TSP individuals

2015 ◽  
Vol 19 (6) ◽  
pp. 578-584 ◽  
Author(s):  
Mariana Tomazini Pinto ◽  
Tathiane Maistro Malta ◽  
Evandra Strazza Rodrigues ◽  
Osvaldo Massaiti Takayanagui ◽  
Yuetsu Tanaka ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Signaling Pathway ◽  
T Cell Receptor ◽  
Cd4 T Cells ◽  
Cell Receptor ◽  
Receptor Signaling ◽  
T Cell Receptor Signaling ◽  
Receptor Signaling Pathway ◽  
Cell Receptor Signaling

scholarly journals The CARMA1-Bcl10 Signaling Complex Selectively Regulates JNK2 Kinase in the T Cell Receptor-Signaling Pathway

Immunity ◽  
2007 ◽  
Vol 26 (1) ◽  
pp. 55-66 ◽  
Author(s):  
Marzenna Blonska ◽  
Bhanu P. Pappu ◽  
Reiko Matsumoto ◽  
Hongxiu Li ◽  
Bing Su ◽  
...  
Keyword(s):  
T Cell ◽  
Signaling Pathway ◽  
T Cell Receptor ◽  
Cell Receptor ◽  
Receptor Signaling ◽  
Signaling Complex ◽  
T Cell Receptor Signaling ◽  
Receptor Signaling Pathway ◽  
Cell Receptor Signaling

scholarly journals CD4+ T Cells Are Required for the Priming of CD8+ T Cells following Infection with Herpes Simplex Virus Type 1

2009 ◽  
Vol 83 (10) ◽  
pp. 5256-5268 ◽  
Author(s):  
Naveen K. Rajasagi ◽  
Sadik H. Kassim ◽  
Christina M. Kollias ◽  
Xiangyi Zhao ◽  
Robert Chervenak ◽  
...  
Keyword(s):  
T Cells ◽  
Herpes Simplex Virus ◽  
Herpes Simplex ◽  
T Cell ◽  
Herpes Simplex Virus Type ◽  
T Cell Response ◽  
Simplex Virus ◽  
T Cell Help ◽  
Hsv 1

ABSTRACT The role of CD4+ helper T cells in modulating the acquired immune response to herpes simplex virus type 1 (HSV-1) remains ill defined; in particular, it is unclear whether CD4+ T cells are needed for the generation of the protective HSV-1-specific CD8+-T-cell response. This study examined the contribution of CD4+ T cells in the generation of the primary CD8+-T-cell responses following acute infection with HSV-1. The results demonstrate that the CD8+-T-cell response generated in the draining lymph nodes of CD4+-T-cell-depleted C57BL/6 mice and B6-MHC-II−/− mice is quantitatively and qualitatively distinct from the CD8+ T cells generated in normal C57BL/6 mice. Phenotypic analyses show that virus-specific CD8+ T cells express comparable levels of the activation marker CD44 in mice lacking CD4+ T cells and normal mice. In contrast, CD8+ T cells generated in the absence of CD4+ T cells express the interleukin 2 receptor α-chain (CD25) at lower levels. Importantly, the CD8+ T cells in the CD4+-T-cell-deficient environment are functionally active with respect to the expression of cytolytic activity in vivo but exhibit a diminished capacity to produce gamma interferon and tumor necrosis factor alpha. Furthermore, the primary expansion of HSV-1-specific CD8+ T cells is diminished in the absence of CD4+-T-cell help. These results suggest that CD4+-T-cell help is essential for the generation of fully functional CD8+ T cells during the primary response to HSV-1 infection.

scholarly journals The Cytotoxic T-Cell Response to Herpes Simplex Virus Type 1 Infection of C57BL/6 Mice Is Almost Entirely Directed against a Single Immunodominant Determinant

1999 ◽  
Vol 73 (9) ◽  
pp. 7619-7626 ◽  
Author(s):  
Morgan E. Wallace ◽  
Rachael Keating ◽  
William R. Heath ◽  
Francis R. Carbone
Keyword(s):  
T Cells ◽  
Herpes Simplex Virus ◽  
Herpes Simplex ◽  
T Cell ◽  
Herpes Simplex Virus Type ◽  
Cell Response ◽  
T Cell Response ◽  
Simplex Virus ◽  
Hsv 1

ABSTRACT Many virus infections give rise to surprisingly limited T-cell responses directed to very few immunodominant determinants. We have been examining the cytotoxic T-lymphocyte (CTL) response to herpes simplex virus type 1 (HSV-1) infection. Previous studies have identified the glycoprotein B-derived peptide from residues 498 to 505 (gB498–505) as one of at least three determinants recognized by HSV-1-specific CTLs isolated from C57BL/6 mice. We had previously found that in vitro-derived CTLs directed to gB498–505 show a characteristic pattern of T-cell receptor (TCR) usage, with 60% of gB498–505-specific CD8+ T cells expressing BV10+ TCR β chains and a further 20% expressing BV8S1. In this report, we confirm that this TCR V-region bias is also reflected in the ex vivo response to HSV-1 infection. A high proportion of activated CD8+draining lymph node cells were found to express these dominant V regions, suggesting that a substantial number of in vivo responding T cells were directed to this one viral determinant. The use of an HSV-1 deletion mutant lacking the gB498–505 determinant in combination with accurate intracellular gamma interferon staining allowed us to quantify the extent of gB-specific T-cell dominance. Together, these results suggested that between 70 and 90% of all CD8+ HSV-1-specific T cells target gB498–505. While deletion of this determinant resulted in an attenuated CD8+ T-cell response, it also permitted the emergence of one or more previously unidentified cryptic specificities. Overall, HSV-1 infection of C57BL/6 mice results in an extremely focused pattern of CD8+ T-cell selection in terms of target specificity and TCR expression.

scholarly journals Natural infection with herpes simplex virus type 1 (HSV-1) induces humoral and T cell responses to the HSV-1 glycoprotein H:L complex

2000 ◽  
Vol 81 (8) ◽  
pp. 2011-2015 ◽  
Author(s):  
Douwe F. Westra ◽  
Georges M. G. M. Verjans ◽  
Albert D. M. E. Osterhaus ◽  
Adriaan van Kooij ◽  
Gjalt W. Welling ◽  
...  
Keyword(s):  
T Cells ◽  
Herpes Simplex Virus ◽  
Herpes Simplex ◽  
T Cell ◽  
Herpes Simplex Virus Type ◽  
T Cell Responses ◽  
Cell Responses ◽  
Simplex Virus ◽  
Hsv 1

The glycoproteins of herpes simplex virus type 1 (HSV-1) are important targets for the immune system in the control of HSV-1 infections. The humoral and T cell responses to the glycoprotein (g)Ht(His):gL complex of HSV-1 were studied in seven HSV-1-seropositive and three HSV-1-seronegative healthy adults. In addition, responses to HSV-1 gDt were determined. As antigens, purified soluble recombinant forms of the gHt(His):gL complex produced by insect cells and of gDt produced by yeast cells were used. In contrast to seronegative donors, sera of all seropositive donors contained gHt(His): gL-specific IgG. Using peripheral blood (PB) T cells, gHt(His):gL-specific proliferative T cell responses were detected in all seropositive donors. Culture supernatants of PB T cells stimulated with recombinant gHt(His):gL contained high levels of interferon-γ and no detectable interleukin-4, indicating their Th1 phenotype. These results show that naturally acquired HSV-1 infection induces gH:gL-specific humoral and T cell responses.

scholarly journals The Novel Oncolytic Herpes Simplex Virus Type-1 (HSV-1) VC2 Promotes Long-lasting, Systemic Anti-melanoma Tumor Immune Responses and Increased Survival in an Immunocompetent B16F10-derived Mouse Melanoma Model

2020 ◽  
Author(s):  
Ifeanyi Kingsley Uche ◽  
Natalie Fowlkes ◽  
Luan Vu ◽  
Tatiane Watanabe ◽  
Mariano Carossino ◽  
...  
Keyword(s):  
T Cells ◽  
Herpes Simplex Virus ◽  
Herpes Simplex ◽  
Response Rates ◽  
Oncolytic Viruses ◽  
Oncolytic Virotherapy ◽  
Oncolytic Herpes Simplex Virus ◽  
Simplex Virus ◽  
Hsv 1

Oncolytic virotherapy (OVT) is now understood to be an immunotherapy that uses viral infection to liberate tumor antigens in an immunogenic context to promote the development of anti-tumor immune responses. The only currently FDA approved oncolytic virotherapy, T-Vec™, is a modified herpes simplex virus type I (HSV-1). While T-Vec™ is associated with limited response rates its modest efficacy supports the continued development of novel OVT viruses. Herein, we test the efficacy of a recombinant HSV-1, VC2, as an OVT in a syngeneic B16F10-derived mouse model of melanoma. VC2 possesses mutations that block its ability to enter neurons via axonal termini. This greatly enhances its safety profile by precluding the virus’s ability to establish latent infection. VC2 has been shown to be a safe, effective vaccine against both HSV-1 and HSV-2 infection in mice, guinea pigs, and non-human primates. We found that VC2 slows tumor growth rates and that VC2 treatment significantly enhances survival of tumor-engrafted, VC2-treated mice over control treatments. VC2-treated mice that survived initial tumor engraftment were resistant to a second engraftment as well as colonization of lungs by intravenous introduction of tumor cells. We found that VC2 treatment induced substantial increases in intratumoral T-cells and a decrease in immunosuppressive T-regulatory cells. This immunity was critically dependent on CD8+ T-cells and less dependent on CD4+ T-cells. Our data provide significant support for the continued development of VC2 as an OVT for the treatment of human and animal cancers. Importance Current oncolytic virotherapies possess limited response rates. However, when certain patient selection criteria are used, oncolytic virotherapy response rates have been shown to increase. This, in addition to the increased response rates of oncolytic virotherapy in combination with other immunotherapies, suggests that oncolytic viruses possess significant therapeutic potential for the treatment of cancer. As such, it is important to continue to develop novel oncolytic viruses as well as support basic research into their mechanisms of efficacy. Our data demonstrate significant clinical potential for VC2, a novel Type 1 oncolytic herpes simplex virus. Additionally, due to the high rates of survival and the dependence on CD8+ T-cells for efficacy, our model will enable study of the immunological correlates of protection for VC2 oncolytic virotherapy and oncolytic virotherapy in general. Understanding the mechanisms of efficacious oncolytic virotherapy will inform the rational design of improved oncolytic virotherapies.

scholarly journals Comprehensive Analysis of Expression Profile and Prognostic Significance of Interferon Regulatory Factors in Pancreatic Cancer

2021 ◽  
Author(s):  
Ke Zhang ◽  
Pan-Ling Xu ◽  
Yu-Jie Li ◽  
Shu Dong ◽  
Hui-Feng Gao ◽  
...  
Keyword(s):  
Pancreatic Cancer ◽  
Immune Response ◽  
T Cells ◽  
Signaling Pathway ◽  
Expression Profile ◽  
Prognostic Significance ◽  
Receptor Signaling ◽  
Regulatory Factors ◽  
Interferon Regulatory Factors ◽  
Receptor Signaling Pathway

Abstract Background: Pancreatic cancer (PC) is a highly lethal disease and an increasing cause of cancer-associated mortality worldwide. Interferon regulatory factors (IRFs) play vital roles in immune response and tumor cellular biological process. However, the specific functions of IRFs in PC and tumor immune response are far from systematically clarified. This study aimed to explorer the expression profile, prognostic significance, and biological function of IRFs in PC.Results: We observed that the level of IRF3, 6, 7, 8, and 9 were elevated in tumor compared to normal tissues in PC. IRF7 expression was significantly associated with patients’ pathology stage in PC. PC patients with high IRF2, low IRF3, and high IRF6 level had significantly poorer overall survival. High mRNA expression, amplification and deep deletion were the three most common types of genetic alterations of IRFs in PC. Low expression of IRF2, 4, 5, and 8 was resistant to most of the drugs or small molecules from Genomics of Drug Sensitivity in Cancer. Moreover, IRFs were positively correlated with the abundance of tumor infiltrating immune cells in PC, including B cells, CD8+ T cells, CD4+ T cells, macrophages, Neutrophil, and Dendritic cells. Functional analysis indicated that IRFs were involved in T cell receptor signaling pathway, immune response and Toll-like receptor signaling pathway. Conclusions: Our results indicated that certain IRFs could serve as potential therapeutic targets and prognostic biomarker for PC patients. Further basic and clinical studies are needed to validate our findings and generalize the clinical application of IRFs in PC.

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