scholarly journals Flagellin synergistically enhances anti-tumor effect of EGFRvIII peptide in a glioblastoma-bearing mouse brain tumor model

2021 ◽  
Author(s):  
Jin Myung Choi ◽  
Sa-Hoe Lim ◽  
Zhi-Peng Liu ◽  
Joon Haeng Rhee ◽  
Mee Sun Yoon ◽  
...  
Keyword(s):  
Brain Tumor ◽  
Survival Rate ◽  
T Cell ◽  
Tumor Growth ◽  
Mouse Brain ◽  
Caspase 3 ◽  
Vibrio Vulnificus ◽  
Tumor Model ◽  
T Cell Response ◽  
Treatment Groups

Abstract Purpose Glioblastoma (GBM) is the most aggressive type of brain tumor with heterogeneity and strong invasive ability. Treatment of GBM has not improved significantly despite the progress of immunotherapy and classical therapy. Epidermal growth factor receptor variant III (EGFRvIII), one of GBM-associated mutants, is regarded as an ideal therapeutic target in EGFRvIII-expressed GBM patients because it is a tumor-specific receptor expressed only in tumors. Flagellin B (FlaB) originated from Vibrio vulnificus is known as a strong adjuvant that enhance innate and adaptive immunity in various vaccine models. This study performed whether FlaB synergistically could enhance the anti-tumor effect of EGFRvIII peptide (PEGFRvIII). Methods EGFRvIII-GL261/Fluc cells were used for glioblastoma-bearing mouse brain model and cell-bearing mice were inoculated with PBS, FlaB alone, PEGFRvIII alone, and PEGFRvIII plus FlaB. Survival rate through tumor growth was investigated by MRI. T cell population was examined by flow cytometry analysis. Both cleaved caspase-3 and CD8+ lymphocytes were shown by immunohistochemistry (IHC) staining. Results The PEGFRvIII plus FlaB group showed delayed tumor growth and increased survival rate when compared to other treatment groups. As an evidence of apoptosis, cleaved caspase-3 expression and DNA disruption were more increased in the PEGFRvIII plus FlaB group than in other groups. In addition, the PEGFRvIII plus FlaB group showed more increased CD8+ T cells and decreased Treg cells than other treatment groups in the brain. Conclusion FlaB can enhance the anti-tumor effect of PEGFRvIII by increasing CD8+ T cell response in a mouse brain GBM model.

scholarly journals CCRL2 promotes antitumor T-cell immunity via amplifying TLR4-mediated immunostimulatory macrophage activation

2021 ◽  
Vol 118 (16) ◽  
pp. e2024171118
Author(s):  
Wei Yin ◽  
Yihong Li ◽  
Yan Song ◽  
Jiarui Zhang ◽  
Chao Wu ◽  
...  
Keyword(s):  
T Cell ◽  
Tumor Growth ◽  
Tumor Model ◽  
T Cell Responses ◽  
T Cell Response ◽  
Tumor Rejection ◽  
Cell Responses ◽  
Cell Immunity ◽  
Potential Biomarker ◽  
Melanoma Growth

Macrophages are the key regulator of T-cell responses depending on their activation state. C-C motif chemokine receptor-like 2 (CCRL2), a nonsignaling atypical receptor originally cloned from LPS-activated macrophages, has recently been shown to regulate immune responses under several inflammatory conditions. However, whether CCRL2 influences macrophage function and regulates tumor immunity remains unknown. Here, we found that tumoral CCRL2 expression is a predictive indicator of robust antitumor T-cell responses in human cancers. CCRL2 is selectively expressed in tumor-associated macrophages (TAM) with immunostimulatory phenotype in humans and mice. Conditioned media from tumor cells could induce CCRL2 expression in macrophages primarily via TLR4, which is negated by immunosuppressive factors. Ccrl2−/− mice exhibit accelerated melanoma growth and impaired antitumor immunity characterized by significant reductions in immunostimulatory macrophages and T-cell responses in tumor. Depletion of CD8+ T cells or macrophages eliminates the difference in tumor growth between WT and Ccrl2−/− mice. Moreover, CCRL2 deficiency impairs immunogenic activation of macrophages, resulting in attenuated antitumor T-cell responses and aggravated tumor growth in a coinjection tumor model. Mechanically, CCRL2 interacts with TLR4 on the cell surface to retain membrane TLR4 expression and further enhance its downstream Myd88-NF-κB inflammatory signaling in macrophages. Similarly, Tlr4−/− mice exhibit reduced CCRL2 expression in TAM and accelerated melanoma growth. Collectively, our study reveals a functional role of CCRL2 in activating immunostimulatory macrophages, thereby potentiating antitumor T-cell response and tumor rejection, and suggests CCLR2 as a potential biomarker candidate and therapeutic target for cancer immunotherapy.

scholarly journals Checkpoint blockade accelerates a novel switch from an NKT-driven TNFα response toward a T cell driven IFN-γ response within the tumor microenvironment

2021 ◽  
Vol 9 (6) ◽  
pp. e002269
Author(s):  
Shota Aoyama ◽  
Ryosuke Nakagawa ◽  
Satoshi Nemoto ◽  
Patricio Perez-Villarroel ◽  
James J Mulé ◽  
...  
Keyword(s):  
Immune Response ◽  
T Cells ◽  
T Cell ◽  
Tumor Growth ◽  
Ex Vivo ◽  
T Cell Response ◽  
Effector Function ◽  
Checkpoint Blockade ◽  
Necrosis Factor Alpha ◽  
Ifn Γ

BackgroundThe temporal response to checkpoint blockade (CB) is incompletely understood. Here, we profiled the tumor infiltrating lymphocyte (TIL) landscape in response to combination checkpoint blockade at two distinct timepoints of solid tumor growth.MethodsC57BL/6 mice bearing subcutaneous MC38 tumors were treated with anti-PD-1 and/or anti-CTLA-4 antibodies. At 11 or 21 days, TIL phenotype and effector function were analyzed in excised tumor digests using high parameter flow cytometry. The contributions of major TIL populations toward overall response were then assessed using ex vivo cytotoxicity and in vivo tumor growth assays.ResultsThe distribution and effector function among 37 distinct TIL populations shifted dramatically between early and late MC38 growth. At 11 days, the immune response was dominated by Tumor necrosis factor alpha (TNFα)-producing NKT, representing over half of all TIL. These were accompanied by modest frequencies of natural killer (NK), CD4+, or CD8+ T cells, producing low levels of IFN-γ. At 21 days, NKT populations were reduced to a combined 20% of TIL, giving way to increased NK, CD4+, and CD8+ T cells, with increased IFN-γ production. Treatment with CB accelerated this switch. At day 11, CB reduced NKT to less than 20% of all TIL, downregulated TNFα across NKT and CD4+ T cell populations, increased CD4+ and CD8+ TIL frequencies, and significantly upregulated IFN-γ production. Degranulation was largely associated with NK and NKT TIL. Blockade of H-2kb and/or CD1d during ex vivo cytotoxicity assays revealed NKT has limited direct cytotoxicity against parent MC38. However, forced CD1d overexpression in MC38 cells significantly diminished tumor growth, suggesting NKT TIL exerts indirect control over MC38 growth.ConclusionsDespite an indirect benefit of early NKT activity, CB accelerates a switch from TNFα, NKT-driven immune response toward an IFN-γ driven CD4+/CD8+ T cell response in MC38 tumors. These results uncover a novel NKT/T cell switch that may be a key feature of CB response in CD1d+ tumors.

scholarly journals Examination of blood–brain barrier (BBB) integrity in a mouse brain tumor model

2012 ◽  
Vol 111 (2) ◽  
pp. 133-143 ◽  
Author(s):  
Ngoc H. On ◽  
Ryan Mitchell ◽  
Sanjot D. Savant ◽  
Corbin. J. Bachmeier ◽  
Grant M. Hatch ◽  
...  
Keyword(s):  
Brain Tumor ◽  
Blood Brain Barrier ◽  
Mouse Brain ◽  
Tumor Model ◽  
Brain Barrier ◽  
Blood Brain ◽  
Brain Tumor Model

scholarly journals Peptide vaccination directed against IDO1-expressing immune cells elicits CD8+ and CD4+ T-cell-mediated antitumor immunity and enhanced anti-PD1 responses

2020 ◽  
Vol 8 (2) ◽  
pp. e000605
Author(s):  
Souvik Dey ◽  
Erika Sutanto-Ward ◽  
Katharina L Kopp ◽  
James DuHadaway ◽  
Arpita Mondal ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Tumor Growth ◽  
Mhc Class I ◽  
Adoptive Transfer ◽  
Immune Cells ◽  
Class Ii ◽  
T Cell Response ◽  
Class I ◽  
Antitumor Effects

BackgroundThe tryptophan-catabolizing enzyme indoleamine 2,3-dioxygenase 1 (IDO1), which subverts T-cell immunity at multiple levels, is itself subject to inherent T-cell reactivity. This intriguing deviation from central tolerance has been interpreted as counterbalancing IDO1-mediated immunosuppression. Based on this hypothesis, clinical studies employing an IDO1 peptide-based vaccine approach for cancer treatment have been initiated, but there remains a pressing need to further investigate the immunological ramifications of stimulating the anti-IDO1 T-cell response in this manner.MethodsCT26 colon carcinoma tumors were evaluated for expression of IDO1 protein by western blot analysis, immunofluorescence microscopy and flow cytometry. Mouse IDO1-derived peptides, predicted to bind either major histocompatibility complex (MHC) class I or II of the H2d BALB/c strain, were emulsified in 50% Montanide for prophylactic or therapeutic vaccine treatment of CT26 tumor-bearing mice initiated either 7 days prior to or following tumor cell injection, respectively. In some therapeutic treatment experiments, administration of programmed cell death protein 1-binding antibody (anti-PD1 antibody) or epacadostat was concurrently initiated. Tumor size was determined by caliper measurements and comparative tumor growth suppression was assessed by longitudinal analyses of tumor growth data. For adoptive transfer, T cells from complete responder animals were isolated using paramagnetic beads and fluorescence-activated cell sorting.ResultsThis study identifies mouse MHC class I-directed and II-directed, IDO1-derived peptides capable of eliciting antitumor responses, despite finding IDO1 expressed exclusively in tumor-infiltrating immune cells. Treatment of established tumors with anti-PD1 antibody and class I-directed but not class II-directed IDO1 peptide vaccines produced an enhanced antitumor response. Likewise, class I-directed and II-directed IDO1 peptides elicited an enhanced combinatorial response, suggesting distinct mechanisms of action. Consistent with this interpretation, adoptive transfer of isolated CD8+ T cells from class I and CD4+ T cells from class II peptide-vaccinated responder mice delayed tumor growth. The class II-directed response was completely IDO1-dependent while the class I-directed response included an IDO1-independent component consistent with antigen spread.ConclusionsThe in vivo antitumor effects demonstrated with IDO1-based vaccines via targeting of the tumor microenvironment highlight the utility of mouse models for further exploration and refinement of this novel vaccine-based approach to IDO1-directed cancer therapy and its potential to improve patient response rates to anti-PD1 therapy.

scholarly journals Stemness of the CT-2A Immunocompetent Mouse Brain Tumor Model: Characterization In Vitro

2012 ◽  
Vol 3 ◽  
pp. 166-174 ◽  
Author(s):  
Emanuela Binello ◽  
Zulekha A. Qadeer ◽  
Harini P. Kothari ◽  
Luni Emdad ◽  
Isabelle M. Germano
Keyword(s):  
Brain Tumor ◽  
Mouse Brain ◽  
Tumor Model ◽  
Immunocompetent Mouse ◽  
Brain Tumor Model

A BRAIN TUMOR MODEL IN THE SYRIAN HAMSTER CHARACTERIZED BY TUMOR GROWTH BUT NON-INVASIVENESS

1996 ◽  
Vol 55 (5) ◽  
pp. 628
Author(s):  
M. T. Curtis ◽  
R. L. Knobler ◽  
J. Gordon ◽  
C. Gonzalez ◽  
S. Vinitski ◽  
...  
Keyword(s):  
Brain Tumor ◽  
Tumor Growth ◽  
Syrian Hamster ◽  
Tumor Model ◽  
Brain Tumor Model

Double Haploidentical Hematopoietic Stem Cell Transplantation (HSCT) Enhances Anti-Tumor Activity After Transplant

Blood ◽  
2012 ◽  
Vol 120 (21) ◽  
pp. 1897-1897
Author(s):  
Tulin Budak-Alpdogan ◽  
Cavan P Bailey ◽  
Michelle Panis ◽  
Christopher Sauter ◽  
Vikas Agrawal ◽  
...  
Keyword(s):  
Bone Marrow ◽  
T Cell ◽  
Tumor Growth ◽  
Low Dose ◽  
Tumor Model ◽  
Tumor Escape ◽  
Tumor Bearing ◽  
Mhc Haplotype ◽  
Anti Tumor Activity

Abstract Abstract 1897 We have previously shown that haploidentical (HI) HSCT with low dose donor T-cell infusion provides a survival advantage in tumor bearing mice when compared to parent F1 or MHC-matched transplant models. We suggest that MHC difference in HI-HSCT generates early T-cell clonal activation against the unshared MHC haplotype, which eliminates residual tumor cells that express the unshared MHC haplotype. However, alteration in MHC antigen expression is a significant contributor to tumor escape from graft-versus-tumor (GVT) activity. Recent haploidentical transplant data revealed that uniparental disomy, the loss of the HLA haplotype, is a clinically relevant mechanism of tumor escape that leads to post-transplant leukemia relapse. Murine renal cell carcinoma, RENCA-TGL, cell line normally expresses only H2Kd as a MHC molecule. Therefore, in our haploidentical transplant model, T cell clonal activity is usually restricted against H2Kd molecule only. For circumventing the single haplotype expression of tumor model, we transfected this cell line with a H2Kb expressing vector, pAcGFP-NeoR-H2Kb, and generated stable clones with G418 selection. The clone that has more than 95% H2Kb expression used for in vivo experiments. Both tumor cell lines, i.e. parental and transfected clone, had similar in vivo tumor growth acceptance and growth rate. We then used two different haploidentical donors that were targeting different MHC haplotypes. Lethally irradiated B6D2F1 (H2Kb/d) mice were transplanted with T cell depleted bone marrow (TCD-BM) from either B6C3F1 (H-2Kb/k) (single haplo-1; SH1), or C3D2F1 (H2Kk/d) (single haplo 2; SH2) or both donor mice with low-dose (1×105) T-cells. In some experiments, animals were also injected either H2Kd or H2Kb/d expressing RENCA-TGL cells for the evaluation of GVT activity. Bone marrow (BM), spleens and thymi were harvested from recipients of single and double HI-HSCT at day 35 and showed similar cellularities. Interestingly, spleen and bone marrow had similar chimerism from both donors in DH-HSCT. There were no early transplant mortality, graft failure, weight loss and GVHD scoring difference among the double or single-haploidentical transplant recipients. In two other sets of experiments, we followed the tumor growth and the survival of tumor bearing mice after transplant. The recipients of DH-HSCT showed a better survival and GVT activity than the recipients of SH-HSCT in RENCA-TGL (H2Kb/d) bearing tumor model. These observations confirmed that MHC targeting plays a prominent role in tumor surveillance, and immune targeting the unshared MHC haplotype with haploidentical transplant induce remarkable survival advantage. Double HI-HSCT provides an unique anti-tumor activity that continues to exert GVT effect, even in case of MHC haplotype loss. Disclosures: No relevant conflicts of interest to declare.

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