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

2016 ◽  
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.

EXTH-72. TRANSLATIONAL INVESTIGATION OF TD139 FOR THE TREATMENT OF HIGH-GRADE MENINGIOMA

2021 ◽  
Vol 23 (Supplement_6) ◽  
pp. vi179-vi180
Author(s):  
Connor Stephenson ◽  
Katie Ross ◽  
William Vandergrift III ◽  
Abhay Varma ◽  
Bruce Frankel ◽  
...  
Keyword(s):  
T Cells ◽  
Tumor Growth ◽  
Cytotoxic T Cells ◽  
Transglutaminase 2 ◽  
Treg Cells ◽  
Orphan Receptor ◽  
High Grade ◽  
Ki 67 ◽  
Western Blots

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.

scholarly journals A Fragrant Environment Containing α-Pinene Suppresses Tumor Growth in Mice by Modulating the Hypothalamus/Sympathetic Nerve/Leptin Axis and Immune System

2019 ◽  
Vol 18 ◽  
pp. 153473541984513 ◽  
Author(s):  
Masatoshi Kusuhara ◽  
Koji Maruyama ◽  
Hidee Ishii ◽  
Yoko Masuda ◽  
Kazutoshi Sakurai ◽  
...  
Keyword(s):  
T Cells ◽  
Immune System ◽  
Tumor Growth ◽  
Sympathetic Nerve ◽  
Stress Hormones ◽  
Nervous Activity ◽  
Underlying Mechanism ◽  
Plasma Corticosterone ◽  
Sympathetic Nervous Activity ◽  
Immunological Parameters

The environment is thought to affect outcomes in patients with cancer; however, this relationship has not been proven directly. Recently, an enriched environment, as a model of a positive environment, has been shown to suppress tumor growth by lowering leptin production through a pathway involving the hypothalamus/sympathetic nerve/leptin axis. We previously reported that a fragrant environment (FE) containing α-pinene suppressed tumor growth in mice; however, the underlying mechanism has not been elucidated. Accordingly, in this study, we investigated changes in the neuroendocrine and immune systems following exposure to an FE. Mice were exposed to α-pinene (5 h/day) for 4 weeks prior to tumor implantation with murine melanoma cells and 3 weeks after transplantation. In addition to the evaluation of tumor growth, the blood, spleen, and hypothalamus were collected 3 weeks after transplantation, and neuroendocrinological and immunological parameters were measured. Tumor size was ~40% smaller in mice exposed to FE. Moreover, plasma noradrenaline concentrations, which reflected sympathetic nervous activity, tended to increase, and leptin levels were significantly decreased in FE-exposed mice. Levels of stress hormones, such as plasma corticosterone and adrenaline, did not change in the 2 groups. In the hypothalamus, brain-derived neurotrophic factor protein levels and glucose-1-phosphate concentrations were decreased in the FE group. Additionally, numbers of B cells, CD4+ T cells, CD8+ T cells, and natural killer cells increased in the FE-exposed mice. These neurohormonal and immunological changes in the FE-exposed mice suggested that the FE may activate the hypothalamus/sympathetic nerve/leptin axis and immune system, thereby retarding tumor growth.

scholarly journals Mathematical model of a personalized neoantigen cancer vaccine and the human immune system

2021 ◽  
Vol 17 (9) ◽  
pp. e1009318
Author(s):  
Marisabel Rodriguez Messan ◽  
Osman N. Yogurtcu ◽  
Joseph R. McGill ◽  
Ujwani Nukala ◽  
Zuben E. Sauna ◽  
...  
Keyword(s):  
Mathematical Model ◽  
T Cells ◽  
Immune System ◽  
Immune Responses ◽  
Cancer Vaccine ◽  
Tumor Size ◽  
Cancer Vaccines ◽  
Patient Specific ◽  
Human Immune System ◽  
Human Immune

Cancer vaccines are an important component of the cancer immunotherapy toolkit enhancing immune response to malignant cells by activating CD4+ and CD8+ T cells. Multiple successful clinical applications of cancer vaccines have shown good safety and efficacy. Despite the notable progress, significant challenges remain in obtaining consistent immune responses across heterogeneous patient populations, as well as various cancers. We present a mechanistic mathematical model describing key interactions of a personalized neoantigen cancer vaccine with an individual patient’s immune system. Specifically, the model considers the vaccine concentration of tumor-specific antigen peptides and adjuvant, the patient’s major histocompatibility complexes I and II copy numbers, tumor size, T cells, and antigen presenting cells. We parametrized the model using patient-specific data from a clinical study in which individualized cancer vaccines were used to treat six melanoma patients. Model simulations predicted both immune responses, represented by T cell counts, to the vaccine as well as clinical outcome (determined as change of tumor size). This model, although complex, can be used to describe, simulate, and predict the behavior of the human immune system to a personalized cancer vaccine.

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

2020 ◽  
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.

scholarly journals Engineering T-Cell Activation for Immunotherapy by Mechanical Forces

2021 ◽  
pp. 553-591
Author(s):  
Elena Locci ◽  
Silvia Raymond
Keyword(s):  
T Cells ◽  
Immune System ◽  
T Cell ◽  
T Cell Activation ◽  
Cell Activation ◽  
Cytotoxic T Cells ◽  
Cancer Therapies ◽  
Physical Barriers ◽  
Keywords Cancer ◽  
New Cancer Therapies

A groundbreaking study led by engineering and medical researchers at the California South University (CSU) shows how immune cells engineered in new cancer therapies can overcome physical barriers so that the patient's own immune system can fight tumors. This research could improve the future of millions of cancer patients worldwide. Immunotherapy, instead of using chemicals or radiation, is a type of cancer treatment that helps the patient's immune system fight cancer. T cells are a type of white blood cell that is essential for the body's immune system. Cytotoxic T cells are like soldiers searching for and destroying target invading cells. Although there has been success in using immunotherapy for some types of cancer in the blood or blood-producing organs, T cell work is much more difficult in solid tumors. Keywords: Cancer; Cells; Tissues, Tumors; Prevention, Prognosis; Diagnosis; Imaging; Screening; Treatment; Management

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

2017 ◽  
Vol 29 (16) ◽  
pp. 6883-6892 ◽  
Author(s):  
Arjyabaran Sinha ◽  
Bong Geun Cha ◽  
Youngjin Choi ◽  
Thanh Loc Nguyen ◽  
Pil J. Yoo ◽  
...  
Keyword(s):  
T Cells ◽  
Tumor Growth ◽  
Cancer Vaccine ◽  
Cytotoxic T Cells

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

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.

scholarly journals Collagen Density Modulates the Immunosuppressive Functions of Tumor-Associated Macrophages

2019 ◽  
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.

scholarly journals Natural Killer Cells: The Linchpin for Successful Cancer Immunotherapy

2021 ◽  
Vol 12 ◽  
Author(s):  
Kari A. Shaver ◽  
Tayler J. Croom-Perez ◽  
Alicja J. Copik
Keyword(s):  
T Cells ◽  
Immune System ◽  
Nk Cells ◽  
Cancer Immunotherapy ◽  
Natural Killer ◽  
Nk Cell ◽  
Checkpoint Inhibitors ◽  
Cytotoxic T Cells ◽  
Current Evidence ◽  
Cell Therapies

Cancer immunotherapy is a highly successful and rapidly evolving treatment modality that works by augmenting the body’s own immune system. While various immune stimulation strategies such as PD-1/PD-L1 or CTLA-4 checkpoint blockade result in robust responses, even in patients with advanced cancers, the overall response rate is low. While immune checkpoint inhibitors are known to enhance cytotoxic T cells’ antitumor response, current evidence suggests that immune responses independent of cytotoxic T cells, such as Natural Killer (NK) cells, play crucial role in the efficacy of immunotherapeutic interventions. NK cells hold a distinct role in potentiating the innate immune response and activating the adaptive immune system. This review highlights the importance of the early actions of the NK cell response and the pivotal role NK cells hold in priming the immune system and setting the stage for successful response to cancer immunotherapy. Yet, in many patients the NK cell compartment is compromised thus lowering the chances of successful outcomes of many immunotherapies. An overview of mechanisms that can drive NK cell dysfunction and hinder immunotherapy success is provided. Rather than relying on the likely dysfunctional endogenous NK cells to work with immunotherapies, adoptive allogeneic NK cell therapies provide a viable solution to increase response to immunotherapies. This review highlights the advances made in development of NK cell therapeutics for clinical application with evidence supporting their combinatorial application with other immune-oncology approaches to improve outcomes of immunotherapies.

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