scholarly journals Glioblastoma Immunotherapy Targeting the Innate Immune Checkpoint CD47-SIRPα Axis

2020 ◽  
Vol 11 ◽  
Author(s):  
Jinyang Hu ◽  
Qungen Xiao ◽  
Minhai Dong ◽  
Dongsheng Guo ◽  
Xudong Wu ◽  
...  
Keyword(s):  
T Cells ◽  
Poor Prognosis ◽  
Antitumor Immunity ◽  
Cytotoxic T Cells ◽  
Innate Immune ◽  
Intracranial Tumors ◽  
Aggressive Form ◽  
Limited Success ◽  
Immunosuppressive Microenvironment

Glioblastoma Multiforme (GBM) is the most common and aggressive form of intracranial tumors with poor prognosis. In recent years, tumor immunotherapy has been an attractive strategy for a variety of tumors. Currently, most immunotherapies take advantage of the adaptive anti-tumor immunity, such as cytotoxic T cells. However, the predominant accumulation of tumor-associated microglia/macrophages (TAMs) results in limited success of these strategies in the glioblastoma. To improve the immunotherapeutic efficacy for GBM, it is detrimental to understand the role of TAM in glioblastoma immunosuppressive microenvironment. In this review, we will discuss the roles of CD47-SIRPα axis in TAMs infiltration and activities and the promising effects of targeting this axis on the activation of both innate and adaptive antitumor immunity in glioblastoma.

scholarly journals Role of Nurr1 in Carcinogenesis and Tumor Immunology: A State of the Art Review

Cancers ◽  
2020 ◽  
Vol 12 (10) ◽  
pp. 3044 ◽  
Author(s):  
Peter Kok-Ting Wan ◽  
Michelle Kwan-Yee Siu ◽  
Thomas Ho-Yin Leung ◽  
Xue-Tang Mo ◽  
Karen Kar-Loen Chan ◽  
...  
Keyword(s):  
T Cells ◽  
Immune Responses ◽  
Antitumor Immunity ◽  
Cytotoxic T Cells ◽  
Early Response ◽  
Downstream Signaling ◽  
Wide Range ◽  
Immunotherapeutic Strategy ◽  
Poor Efficacy

Nuclear receptor related-1 protein (Nurr1), coded by an early response gene, is involved in multiple cellular and physiological functions, including proliferation, survival, and self-renewal. Dysregulation of Nurr1 has been frequently observed in many cancers and is attributed to multiple transcriptional and post-transcriptional mechanisms. Besides, Nurr1 exhibits extensive crosstalk with many oncogenic and tumor suppressor molecules, which contribute to its potential pro-malignant behaviors. Furthermore, Nurr1 is a key player in attenuating antitumor immune responses. It not only potentiates immunosuppressive functions of regulatory T cells but also dampens the activity of cytotoxic T cells. The selective accessibility of chromatin by Nurr1 in T cells is closely associated with cell exhaustion and poor efficacy of cancer immunotherapy. In this review, we summarize the reported findings of Nurr1 in different malignancies, the mechanisms that regulate Nurr1 expression, and the downstream signaling pathways that Nurr1 employs to promote a wide range of malignant phenotypes. We also give an overview of the association between Nurr1 and antitumor immunity and discuss the inhibition of Nurr1 as a potential immunotherapeutic strategy.

scholarly journals Immune Modulatory Short Noncoding RNAs Targeting the Glioblastoma Microenvironment

2021 ◽  
Vol 11 ◽  
Author(s):  
Jun Wei ◽  
Eli Gilboa ◽  
George A. Calin ◽  
Amy B. Heimberger
Keyword(s):  
Blood Brain Barrier ◽  
Immune Suppression ◽  
Immune Cells ◽  
Poor Prognosis ◽  
Immune Modulation ◽  
Antitumor Immunity ◽  
Noncoding Rnas ◽  
Delivery Vehicles ◽  
Immunosuppressive Microenvironment

Glioblastomas are heterogeneous and have a poor prognosis. Glioblastoma cells interact with their neighbors to form a tumor-permissive and immunosuppressive microenvironment. Short noncoding RNAs are relevant mediators of the dynamic crosstalk among cancer, stromal, and immune cells in establishing the glioblastoma microenvironment. In addition to the ease of combinatorial strategies that are capable of multimodal modulation for both reversing immune suppression and enhancing antitumor immunity, their small size provides an opportunity to overcome the limitations of blood-brain-barrier (BBB) permeability. To enhance glioblastoma delivery, these RNAs have been conjugated with various molecules or packed within delivery vehicles for enhanced tissue-specific delivery and increased payload. Here, we focus on the role of RNA therapeutics by appraising which types of nucleotides are most effective in immune modulation, lead therapeutic candidates, and clarify how to optimize delivery of the therapeutic RNAs and their conjugates specifically to the glioblastoma microenvironment.

scholarly journals The abscopal effect of radiation therapy

2021 ◽  
Vol 17 (13) ◽  
pp. 1683-1694
Author(s):  
Daniel J Craig ◽  
Nisha S Nanavaty ◽  
Monika Devanaboyina ◽  
Laura Stanbery ◽  
Danae Hamouda ◽  
...  
Keyword(s):  
T Cells ◽  
Radiation Therapy ◽  
Cytotoxic T Cells ◽  
Cell Activity ◽  
The Body ◽  
Abscopal Effect ◽  
Sting Pathway ◽  
And Migration ◽  
Anticancer Response

Radiation therapy (RT) in some cases results in a systemic anticancer response known as the abscopal effect. Multiple hypotheses support the role of immune activation initiated by RT-induced DNA damage. Optimal radiation dose is necessary to promote the cGAS-STING pathway in response to radiation and initiate an IFN-1 signaling cascade that promotes the maturation and migration of dendritic cells to facilitate antigen presentation and stimulation of cytotoxic T cells. T cells then exert a targeted response throughout the body at areas not subjected to RT. These effects are further augmented through the use of immunotherapeutic drugs resulting in increased T-cell activity. Tumor-infiltrating lymphocyte presence and TREX1, KPNA2 and p53 signal expression are being explored as prognostic biomarkers.

KIR Positive Subsets of Human CD56+CD3+ NKT Cells Are Different in Frequency from Equivalant KIR Positive CD56+CD3- NK Cell Subsets.

Blood ◽  
2007 ◽  
Vol 110 (11) ◽  
pp. 3878-3878
Author(s):  
Ilka Bondzio ◽  
Andreas Arendt ◽  
Jurgen Schmitz ◽  
Volker Huppert
Keyword(s):  
T Cells ◽  
Nk Cells ◽  
Nk Cell ◽  
Cytotoxic T Cells ◽  
Killer Cell ◽  
Nkt Cells ◽  
Nkt Cell ◽  
Cell Clones ◽  
Number Of Publications

Abstract Killer cell immunoglobulin-like receptors (KIRs) are known to modulate the cytotoxic ability of human Natural Killer (NK) cells, as well as a subset of T cells. To date, only a very small number of publications have discussed the role of KIRs on T cells, e.g. CMV-specific CD4+CD28-KIR+ cytotoxic T cells (van Bergen, J., J Immunol. 2004), so we investigated whether CD56+CD3+ NKT cells might also have KIR-positive subsets. Whole human blood as well as magnetically sorted human CD56+CD3+ NKT cells were analyzed for their expression of various KIR molecules using a novel panel of fluorochrome-conjugated, anti-KIR monoclonal antibodies (CD158a/h (KIR2DL1/DS1), CD158b (KIR2DL2), CD158e (KIR3DL1), CD158i (KIR2DS4), KIR2D; Miltenyi Biotec). KIR-positive CD56+CD3+ NKT cells were identified in every donor tested. Donors possessing NK cells of a specific KIR phenotype also possessed CD56+CD3+ NKT cells with the same KIR phenotype. KIRs were also expressed in a clonal fashion on CD56+CD3+ NKT cells, similarly to NK cells. The investigated KIRs were also shown to be expressed on unseparated NK and CD56+CD3+ NKT cells from whole blood. In addition, the ratio between KIR expression on NK and CD56+CD3+ NKT cells was calculated for each donor analyzed. The results show that there is no correlation between the frequencies of KIR expression on NK cells with that of CD56+CD3+ NKT cells. For example, the expression of CD158a/h in one donor was found to be the highest of all CD56+CD3+ NKT cells analyzed, but the lowest of all NK cells by comparison to the other donors tested. For all KIR phenotypes analyzed, the frequency of KIR+ NK cells was higher than the frequency of KIR+ CD56+CD3+ NKT cells in all samples (range: 1.1 to 25.3-fold higher). Interestingly, the frequency of KIR+ NK cells versus KIR+ CD56+CD3+ NKT cells differs significantly between donors: in one donor the frequency of KIR expression is between 7.3 to 25.3-fold higher in NK cells for multiple KIR phenotypes, while this range is more narrow in other donors (2.0–5.4-fold higher). The frequencies of CD56+CD3+ NKT cell subsets staining positive for particular KIRs differ significantly between donors, e.g. for CD158b, the number of positive CD56+CD3+ NKT cells fall within a range of 4.8% to 43.3%. For CD56+CD3+ NKT cells sorted with MACS® Technology, a similarly wide-ranging distribution of CD158b (KIR2DL2) expression was found (0.85%–5.82%), though at a lower level. Further research will be required to explore these differences as they may point to different mechanisms of KIR regulation. The identification of KIR-positive CD56+CD3+ NKT cells may also provide an opportunity for their use for functional KIR studies instead of NK cell clones, as the cloning of CD56+CD3+ NKT cells may prove easier (i.e. using standard T cell cloning methods) than that of NK cells.

A Critical Role for Innate Immunity In Allogeneic Hematopoietic Cell Rejection Via the TLR4/TRIF Pathway

Blood ◽  
2010 ◽  
Vol 116 (21) ◽  
pp. 77-77
Author(s):  
Hong Xu ◽  
Jun Yan ◽  
Ziqiang Zhu ◽  
Yiming Huang ◽  
Yujie Wen ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Innate Immunity ◽  
T Cells ◽  
Immune System ◽  
T Cell ◽  
Innate Immune System ◽  
Critical Role ◽  
Innate Immune ◽  
Wild Type

Abstract Abstract 77 Adaptive immunity, especially T cells, has long been believed to be the dominant immune barrier in allogeneic transplantation. Targeting host T cells significantly reduces conditioning for bone marrow cell (BMC) engraftment. Innate immunity has been recently shown to pose a significant barrier in solid organ transplantation, but has not been addressed in bone marrow transplantation (BMT). Using T cell deficient (TCR-β/δ−/−) or T and B cell deficient (Rag−/−) mice, we found that allogeneic BMC rejection occurred early before the time required for T cell activation and was T- and B-cell independent, suggesting an effector role for innate immune cells in BMC rejection. Therefore, we hypothesized that by controlling both innate and adaptive immunity, the donor BMC would have a window of advantage to engraft. Survival of BMC in vivo was significantly improved by depleting recipient macrophages and/or NK cells, but not neutrophils. Moreover, depletion of macrophages and NK cells in combination with co-stimulatory blockade with anti-CD154 and rapamycin as a novel form of conditioning resulted in 100% allogeneic engraftment without any irradiation and T cell depletion. Donor chimerism remained stable and durable up to 6 months. Moreover, specific Vβ5½ and Vβ11 clonal deletion was detected in host CD4+ T cells in chimeras, indicating central tolerance to donor alloantigens. Whether and how the innate immune system recognizes or responds to allogeneic BMCs remains unknown. Toll-like receptors (TLRs) are a class of proteins that play a key role in the innate immune system. The signaling function of TLR depends on intracellular adaptors. The adaptor MyD88 transmits signals emanating from all TLR, except TLR3 while TRIF specifically mediates TLR3 and TLR4 signaling via type 1 IFN. To further determine the innate signaling pathways in allogeneic BMC rejection, B6 background (H2b) MyD88−/− and TRIF−/− mice were conditioned with anti-CD154/rapamycin plus 100 cGy total body irradiation and transplanted with 15 × 106 BALB/c (H2d) BMC. Only 33.3% of MyD88−/− recipients engrafted at 1 month, resembling outcomes for wild-type B6 mice. In contrast, 100% of TRIF−/− mice engrafted. The level of donor chimerism in TRIF−/− mice was 5.1 ± 0.6% at one month, significantly higher than in MyD88−/− and wild-type B6 controls (P < 0.005). To determine the mechanism of innate signaling in BMC rejection, we examined whether TRIF linked TLR3 or TLR4 is the key pattern recognition receptor involved in BMC recognition. To this end, TLR3−/− and TLR4−/− mice were transplanted with BALB/c BMC with same conditioning. None of the TLR3−/− mice engrafted. In contrast, engraftment was achieved in 100% of TLR4−/− mice up to 6 months follow up. Taken together, these results suggest that rejection of allogeneic BMC is uniquely dependent on the TLR4/TRIF signaling pathway. Thus, our results clearly demonstrate a previously unappreciated role for innate immunity in allogeneic BMC rejection. Our current findings are distinct from prior reports demonstrating a critical role of MyD88 in rejection of allogeneic skin grafts and lung, and may reflect unique features related to BMC. The findings of the role of innate immunity in BMC rejection would lead to revolutionary changes in our understanding and management of BMT. This would be informative in design of more specific innate immune targeted conditioning proposals in BMT to avoid the toxicity. Disclosures: Bozulic: Regenerex LLC: Employment. Ildstad:Regenerex LLC: Equity Ownership.

DOCK8-Deficient Mice Reveal a Crucial Role for Dendritic Cell Activity in the Initiation of the Allogeneic Response to Transfused Red Blood Cells

Blood ◽  
2015 ◽  
Vol 126 (23) ◽  
pp. 658-658
Author(s):  
Stephanie C. Eisenbarth ◽  
Jeanne E. Hendrickson ◽  
Samuele Calabro ◽  
Antonia Gallman
Keyword(s):  
T Cells ◽  
Dendritic Cells ◽  
T Cell ◽  
Dendritic Cell ◽  
T Cell Activation ◽  
Cell Activation ◽  
Innate Immune ◽  
Allogeneic Response ◽  
Deficient Mice

Abstract The generation of antibodies against transfused red blood cells (RBCs) can pose a serious health risk, especially in chronically transfused patients requiring life-long transfusion support; yet our understanding of what immune signals or cells dictate when someone will become alloimmunized is lacking. The relative role of dendritic cells, B cells and macrophages in the induction of RBC alloimmunization remain unclear. Given the now well established role of innate immune signals in regulating adaptive immunity, understanding if and how innate immunity is triggered during transfusion may allow development of therapies to prevent alloimmunization in chronically transfused subjects such as those with myelodysplasia or hemoglobinopathies. We have established a murine model system in which we can evaluate both the role of particular innate immune stimuli as well as particular cells of the immune system in regulating the allogeneic response to transfused RBCs. A particularly useful transgenic "HOD mouse" has been engineered, which encodes a triple fusion protein and provides a unique tool to directly assess both RBC-specific T and B cell responses. This RBC-specific antigen contains the model protein antigen hen egg lysozyme (HEL) fused to chicken ovalbumin (OVA) fused to the human Duffyb blood group antigen (HEL-OVA-Duffy) as an integral membrane protein under control of the beta globin promoter. Transfusion of genetically targeted mice lacking various innate immune cells or receptors allows us to screen for important immune pathways regulating the response to allogeneic RBCs. Using these models, we recently discovered that mice lacking the GEF (guanine nucleotide exchange factor) DOCK8 fail to develop alloimmunity to transfused RBCs. Dendritic cells in these knockout mice fail to migrate to T cells due to lack of coordinated actin rearrangement governed by this GEF. Both B cell and T cell activation in the spleen to the transgenic transfused RBCs is abrogated. Inclusion of OVA in the alloantigen of the HOD mice allows us to readily study naïve CD4+ T cell activation following transfusion by using the OTII T cell receptor (TCR) transgenic mice in which essentially all T cells express one antigen receptor specific for a peptide of OVA. By tracking rounds of cell division we found that adoptively transferred OTII undergo more than 5-8 rounds of division in the spleen three days following transfusion of HOD RBCs in WT recipients. In contrast, no OTII proliferation was observed in DOCK8-deficient mice following OTII adoptive transfer and HOD RBC transfusion, suggesting that T cells are failing to receive activation signals by splenic antigen presenting cells. Our preliminary data now suggest that DOCK8-deficient dendritic cells are able to process and present RBC-derived antigens, but do not migrate to T cell zones in the spleen to prime naïve RBC-specific T cells. The need for dendritic cell migration within the spleen in the induction of alloimmunity to transfused RBCs has not been addressed; these mice allow us for the first time to answer these fundamental immunologic questions during transfusion. Future work will aim to determine how dendritic cell movement within the spleen is regulated during transfusion and the specific role of splenic dendritic cell subsets in CD4+ T cell priming to allogeneic RBCs. Disclosures No relevant conflicts of interest to declare.

HPV16E7-HSP70 hybrid DNA vaccine induces E7-specific cytotoxic T cells and antitumor immunity

2006 ◽  
Vol 11 (3) ◽  
pp. 749-755
Author(s):  
Zhu Liqin ◽  
Li Hui ◽  
Xiong Jinhu ◽  
Wang Tongxiang ◽  
Ou Xuan ◽  
...  
Keyword(s):  
T Cells ◽  
Dna Vaccine ◽  
Antitumor Immunity ◽  
Cytotoxic T Cells ◽  
Hybrid Dna
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