Carbohydrate-Functionalized rGO as an Effective Cancer Vaccine for Stimulating Antigen-Specific Cytotoxic T Cells and Inhibiting Tumor Growth

Abstract BACKGROUND High-Grade Meningioma (HGM), such as atypical and anaplastic meningiomas, represent a subgroup of meningiomas with histologic and clinical features suggesting aggressive behavior with a penchant for recurrence, even after surgical resection. Here, we postulate that high levels of Galectin-3 (Gal-3) affect the cellular composition and are at the root of the profoundly immunosuppressive tumor microenvironment of HGM. Our study aimed to validate the effect of the Gal-3 inhibitor (TD139) in in vivo. METHODS In vivo MGS2 murine models of HGM were utilized to assess efficacy of treatment with TD139 via intravenous injection. We used ELISA spot, RT-PCR and western blots techniques. MRI and immunohistochemistry -staining methods were used to detect tumor growth in in vivo following TD139 treatments. RESULTS Our results demonstrated a significantly elevated level of Gal-3 in both HGM tissue and serum when compared to non-tumor patients. Furthermore, Epithelial membrane antigen, Ki-67, and Transglutaminase 2 were highly expressed in HGM, whereas the number of observed cytotoxic T-cells in HGM was markedly decreased. When human PBMCs were activated with anti-CD3 (1µg/ml) and anti-CD28 (2µg/ml) antibodies and treated with recombinant Gal-3 protein (500ng/ml) for 96hr, we found reduced expression of T-Box Transcription Factor 21 and RAR Related Orphan Receptor C mRNA with concurrent upregulated expression of GATA Binding protein 3 and Forkhead box P3 mRNA. These findings support the concept that Gal-3 skews the differentiation of CD4+ T cells towards Th2 and Treg cells. In vivo treatment of TD139 (1mg/kg per day for 14 days) showed significant decrease (∼35%) in MGS2 tumor growth in orthotopic allograft model (at Day 41) and increased survival via multiple mechanism. Additionally, we observed an upregulation of CD38 (M1 macrophages) and CD8+ T cells in treated cells. CONCLUSIONS These findings suggest that TD139 may be an effective approach in the treatment of HGM patients.

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Activating a collaborative innate-adaptive immune response to control breast and ovarian cancer metastasis

10.1101/2020.07.13.200477 ◽

2020 ◽

Cited By ~ 1

Author(s):

Lijuan Sun ◽

Tim Kees ◽

Ana Santos Almeida ◽

Bodu Liu ◽

Xue-Yan He ◽

...

Keyword(s):

Immune Response ◽

T Cells ◽

Tumor Growth ◽

Cancer Cells ◽

Cancer Metastasis ◽

Cytotoxic T Cells ◽

Interleukin 12 ◽

Type I ◽

Monophosphoryl Lipid A ◽

Response To Chemotherapy

AbstractMany cancers recruit monocytes/macrophages and polarize them into tumor-associated macrophages (TAMs). TAMs promote tumor growth and metastasis and inhibit cytotoxic T cells. Yet, macrophages can also kill cancer cells after polarization by e.g., lipopolysaccharide (LPS, a bacteria-derived toll-like receptor 4 [TLR4] agonist) and interferon gamma (IFNγ). They do so via nitric oxide (NO), generated by inducible NO synthase (iNOS). Altering the polarization of macrophages could therefore be a strategy for controlling cancer. Here, we show that monophosphoryl lipid A (MPLA, a derivative of LPS) with IFNγ activated macrophages isolated from metastatic pleural effusions of breast cancer patients to kill the corresponding patients’ cancer cells in vitro. Importantly, intratumoral injection of MPLA with IFNγ not only controlled local tumor growth but also reduced metastasis in mouse models of luminal and triple negative breast cancers. Furthermore, intraperitoneal administration of MPLA with IFNγ reprogrammed peritoneal macrophages, suppressed metastasis, and enhanced the response to chemotherapy in the ID8-p53−/− ovarian carcinoma mouse model. The combined MPLA+IFNγ treatment reprogrammed the immunosuppressive microenvironment to be immunostimulatory by recruiting leukocytes, stimulating type I interferon signaling, decreasing tumor-associated (CD206+) macrophages, increasing tumoricidal (iNOS+) macrophages, and activating cytotoxic T cells through macrophage-secreted interleukin 12 (IL-12) and tumor necrosis factor α (TNFα). Both macrophages and T cells were critical for the anti-metastatic effects of MPLA+IFNγ. MPLA and IFNγ are already used individually in clinical practice, so our strategy to engage the anti-tumor immune response, which requires no knowledge of unique tumor antigens, may be ready for near-future clinical testing.

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Non-linear tumor-immune interactions arising from spatial metabolic heterogeneity

10.1101/038273 ◽

2016 ◽

Cited By ~ 4

Author(s):

Mark Robertson-Tessi ◽

Robert J. Gillies ◽

Robert A. Gatenby ◽

Alexander R. A. Anderson

Keyword(s):

Mathematical Model ◽

T Cells ◽

Immune System ◽

Tumor Growth ◽

Cytotoxic T Cells ◽

Non Linear ◽

Metabolic Heterogeneity ◽

Multiscale Mathematical Model ◽

Tumor Phenotypes

AbstractA hybrid multiscale mathematical model of tumor growth is used to investigate how tumoral and microenvironmental heterogeneity affect the response of the immune system. The model includes vascular dynamics and evolution of metabolic tumor phenotypes. Cytotoxic T cells are simulated, and their effect on tumor growth is shown to be dependent on the structure of the microenvironment and the distribution of tumor phenotypes. Importantly, no single immune strategy is best at all stages of tumor growth.

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An NF-κB/IRF1 axis programs cDC1s to drive anti-tumor immunity

10.1101/2020.12.28.424621 ◽

2020 ◽

Author(s):

G Ghislat ◽

AS Cheema ◽

E Baudoin ◽

C Verthuy ◽

PJ Ballester ◽

...

Keyword(s):

T Cells ◽

Tumor Growth ◽

Single Cell ◽

Signaling Pathways ◽

Tumor Immunity ◽

Focal Point ◽

Cytotoxic T Cells ◽

Cytokines And Chemokines ◽

And Control

AbstractConventional type 1 dendritic cells (cDC1s) are critical for anti-tumor immunity. They acquire antigens from dying tumor cells and cross-present them to CD8+ T cells, promoting the expansion of tumor-specific cytotoxic T cells. However, the signaling pathways that govern the anti-tumor functions of cDC1s are poorly understood. We mapped the molecular pathways regulating intra-tumoral cDC1 maturation using single cell RNA sequencing. We identified NF-κB and IFN pathways as being highly enriched in a subset of functionally mature cDC1s. The specific targeting of NF-κB or IFN pathways in cDC1s prevented the recruitment and activation of CD8+ T cells and the control of tumor growth. We identified an NF-κB-dependent IFNγ-regulated gene network in cDC1s, including cytokines and chemokines specialized in the recruitment and activation of cytotoxic T cells. We used single cell transcriptomes to map the trajectory of intra-tumoral cDC1 maturation which revealed the dynamic reprogramming of tumor-infiltrating cDC1s by NF-κB and IFN signaling pathways. This maturation process was perturbed by specific inactivation of either NF-κB or IRF1 in cDC1s, resulting in impaired expression of IFN-γ-responsive genes and consequently a failure to efficiently recruit and activate anti-tumoral CD8+ T cells. Finally, we demonstrate the relevance of these findings to cancer patients, showing that activation of the NF-κB/IRF1 axis in association with cDC1s is linked with improved clinical outcome. The NF-κB/IRF1 axis in cDC1s may therefore represent an important focal point for the development new diagnostic and therapeutic approaches to improve cancer immunotherapy.One Sentence SummaryNF-κB and IRF1 coordinate intra-tumoral cDC1 maturation and control of immunogenic tumor growth.

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Collagen Density Modulates the Immunosuppressive Functions of Tumor-Associated Macrophages

10.1101/513986 ◽

2019 ◽

Cited By ~ 2

Author(s):

Anne Mette H. Larsen ◽

Dorota E. Kuczek ◽

Adrija Kalvisa ◽

Majken S. Siersbæk ◽

Marie-Louise Thorseth ◽

...

Keyword(s):

T Cells ◽

T Cell ◽

Tumor Growth ◽

Poor Prognosis ◽

Cytotoxic T Cells ◽

Raw 264.7 ◽

Macrophage Phenotype ◽

Tumor Associated Macrophages ◽

Murine Bone Marrow ◽

Collagen Density

AbstractTumor-associated macrophages (TAMs) support tumor growth by suppressing the activity of tumor infiltrating T cells. Consistently, the number of TAMs has been correlated with a poor prognosis of cancer. The immunosuppressive TAMs are also considered a major limitation for the efficacy of cancer immunotherapy. However, the molecular reason behind the acquisition of an immunosuppressive TAM phenotype is still not completely understood. During solid tumor growth, the extracellular matrix (ECM) is degraded and substituted with a tumor specific collagen-rich ECM. The collagen density of this tumor ECM has been associated with a poor prognosis of several cancers, but the underlying reason for this correlation is not well understood. Here, we have investigated whether the collagen density could modulate the immunosuppressive activity of TAMs and thereby promote tumor progression.In this study, the macrophage cell line RAW 264.7 was 3D cultured in collagen matrices of low- and high collagen densities mimicking healthy and tumor tissue, respectively. The effects of collagen density on macrophage phenotype and function were investigated by confocal microscopy, flow cytometry, RNA sequencing, qRT-PCR, and ELISA analysis. To investigate the effect of collagen density on the immune modulatory activity of macrophages, co-culture assays with primary T cells to assess T cell chemotaxis and proliferation were conducted. Lastly, the effects of collagen density on primary cells were investigated using murine bone-marrow derived macrophages (BMDMs) and TAMs isolated from murine 4T1 breast tumors.Collagen density did not affect the proliferation, viability or morphology of macrophages. However, whole-transcriptome analysis revealed a striking response to the surrounding collagen density including the differential regulation of many immune regulatory genes and genes encoding chemokines. The transcriptional changes in RAW 264.7 macrophages were shown to be similar in murine BMDMs and TAMs. Strikingly, the collagen density-induced changes in the gene expression profile had functional consequences for the macrophages. Specifically, macrophages cultured in high density collagen were less efficient at attracting cytotoxic T cells and also capable of inhibiting T cell proliferation to a greater extent than macrophages cultured in low density collagen.Our study demonstrates that a high collagen density can instruct TAMs to acquire an immunosuppressive phenotype. This could be one of the mechanisms decreasing the efficacy of immunotherapy and linking increased collagen density to poor patient prognosis.

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Experimental analysis of T cell epitopes for designing liver cancer vaccine predicted by system-level immunoinformatics approach

AJP Gastrointestinal and Liver Physiology ◽

10.1152/ajpgi.00068.2020 ◽

2020 ◽

Vol 318 (6) ◽

pp. G1055-G1069

Author(s):

Syed Aun Muhammad ◽

Sidra Zafar ◽

Samana Zahra Rizvi ◽

Imran Imran ◽

Fahad Munir ◽

...

Keyword(s):

T Cells ◽

T Cell ◽

Liver Cancer ◽

Cancer Vaccine ◽

Experimental Analysis ◽

Cytotoxic T Cells ◽

System Level ◽

T Cell Epitopes ◽

Serum Samples ◽

Effector Molecules

We observed substantial high levels of granzymes B in serum samples of component C6 (C6) and albumin (ALB) compared with control, indicating the activity of cytotoxic T cells. We concluded that C6 and ALB are likely to contain potential epitopes for the induction of protective effector molecules, supporting the feasibility of therapeutic peptide-based vaccine for liver cancer.

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Cytotoxic T-cells mediate exercise-induced reductions in tumor growth

eLife ◽

10.7554/elife.59996 ◽

2020 ◽

Vol 9 ◽

Cited By ~ 1

Author(s):

Helene Rundqvist ◽

Pedro Veliça ◽

Laura Barbieri ◽

Paulo A Gameiro ◽

David Bargiela ◽

...

Keyword(s):

T Cells ◽

Tumor Growth ◽

Tumor Progression ◽

Cd8 T Cells ◽

Cytotoxic T Cells ◽

Central Carbon Metabolism ◽

Effector Cells ◽

Wide Range ◽

Exercise Induced

Exercise has a wide range of systemic effects. In animal models, repeated exertion reduces malignant tumor progression, and clinically, exercise can improve outcome for cancer patients. The etiology of the effects of exercise on tumor progression are unclear, as are the cellular actors involved. We show here that in mice, exercise-induced reduction in tumor growth is dependent on CD8+ T cells, and that metabolites produced in skeletal muscle and excreted into plasma at high levels during exertion in both mice and humans enhance the effector profile of CD8+ T-cells. We found that activated murine CD8+ T cells alter their central carbon metabolism in response to exertion in vivo, and that immune cells from trained mice are more potent antitumor effector cells when transferred into tumor-bearing untrained animals. These data demonstrate that CD8+ T cells are metabolically altered by exercise in a manner that acts to improve their antitumoral efficacy.

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Author response: Cytotoxic T-cells mediate exercise-induced reductions in tumor growth

10.7554/elife.59996.sa2 ◽

2020 ◽

Author(s):

Helene Rundqvist ◽

Pedro Veliça ◽

Laura Barbieri ◽

Paulo A Gameiro ◽

David Bargiela ◽

...

Keyword(s):

T Cells ◽

Tumor Growth ◽

Cytotoxic T Cells ◽

Author Response ◽

Exercise Induced

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Decision letter: Cytotoxic T-cells mediate exercise-induced reductions in tumor growth

10.7554/elife.59996.sa1 ◽

2020 ◽

Author(s):

Randy Hampton

Keyword(s):

T Cells ◽

Tumor Growth ◽

Cytotoxic T Cells ◽

Exercise Induced

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What is Cancer Vaccine? Does it prevent Cancer?

10.31219/osf.io/vj2c6 ◽

2020 ◽

Author(s):

Dattatreya Mukherjee

Keyword(s):

Breast Cancer ◽

T Cells ◽

Targeted Therapy ◽

Cancer Vaccine ◽

Cytotoxic T Cells ◽

Cleveland Clinic ◽

Therapeutic Vaccine ◽

Basic Mechanism ◽

Preventive Vaccine ◽

Common Term

Cancer vaccine is a very common term for many people after FDA approved theTriple Negative Breast Cancer based vaccine of Cleveland Clinic, USA. So what is aCancer Vaccine and do it prevent cancer. Lets discuss these in this article.First Cancer Vaccine is not a preventive vaccine, its a therapeutic vaccine. What doesit means? It means it will increase the immunity against the tumor cells i.e its a partof immuno-targeted therapy. Now how does it works?Basic mechanism is the process to increase the amount of T cells against TumorAssociated Antigen (TAA). Mostly DNA/RNA/DC/CART are used to activate MHCI and II and thus increase CD4 helper and CD8 cytotoxic T cells Or use somemodified peptide or virus (Oncolytic Vaccine) to get the same mechanism.

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