scholarly journals Adenosine 2A receptor and TIM3 suppress cytolytic killing of tumor cells via cytoskeletal polarization

2022 ◽  
Vol 5 (1) ◽  
Author(s):  
Grace L. Edmunds ◽  
Carissa C. W. Wong ◽  
Rachel Ambler ◽  
Emily J. Milodowski ◽  
Hanin Alamir ◽  
...  
Keyword(s):  
Tumor Cells ◽  
Tumor Response ◽  
Ex Vivo ◽  
Cytotoxic T Cells ◽  
Tumor Model ◽  
Cell Type ◽  
Adenosine 2A Receptor ◽  
Tumor Cell Killing

AbstractTumors generate an immune-suppressive environment that prevents effective killing of tumor cells by CD8+ cytotoxic T cells (CTL). It remains largely unclear upon which cell type and at which stage of the anti-tumor response mediators of suppression act. We have combined an in vivo tumor model with a matching in vitro reconstruction of the tumor microenvironment based on tumor spheroids to identify suppressors of anti-tumor immunity that directly act on interaction between CTL and tumor cells and to determine mechanisms of action. An adenosine 2A receptor antagonist, as enhanced by blockade of TIM3, slowed tumor growth in vivo. Engagement of the adenosine 2A receptor and TIM3 reduced tumor cell killing in spheroids, impaired CTL cytoskeletal polarization ex vivo and in vitro and inhibited CTL infiltration into tumors and spheroids. With this role in CTL killing, blocking A2AR and TIM3 may complement therapies that enhance T cell priming, e.g. anti-PD-1 and anti-CTLA-4.

scholarly journals The adenosine 2a receptor and TIM3 directly inhibit killing of tumor cells by cytotoxic T lymphocytes through interference with cytoskeletal polarization

2021 ◽  
Author(s):  
Grace L. Edmunds ◽  
Carissa W.L. Wong ◽  
Rachel Ambler ◽  
Emily Milodowski ◽  
Hanin Alamir ◽  
...  
Keyword(s):  
Tumor Cells ◽  
Tumor Response ◽  
Ex Vivo ◽  
Cytotoxic T Cells ◽  
Tumor Model ◽  
Cell Type ◽  
Adenosine 2A Receptor ◽  
Tumor Cell Killing

Tumors generate an immune-suppressive environment that prevents effective killing of tumor cells by CD8+ cytotoxic T cells (CTL). It remains largely unclear upon which cell type and at which stage of the anti-tumor response mediators of suppression act. We have combined an in vivo tumor model with a matching in vitro reconstruction of the tumor microenvironment based on tumor spheroids to identify suppressors of anti-tumor immunity that directly act on interaction between CTL and tumor cells and to determine mechanisms of action. An adenosine 2a receptor antagonist, as enhanced by blockade of TIM3, slowed tumor growth in vivo. Engagement of the adenosine 2a receptor and TIM3 reduced tumor cell killing in spheroids, impaired CTL cytoskeletal polarization ex vivo and in vitro and inhibited CTL infiltration into tumors and spheroids. With this focus on CTL killing, blocking A2aR and TIM3 complements therapies that enhance T cell priming, e.g. anti-PD1 and anti-CTLA-4.

Monoclonal antibody 2C5-mediated binding of liposomes to brain tumor cells in vitro and in subcutaneous tumor model in vivo

2005 ◽  
Vol 13 (6) ◽  
pp. 337-343 ◽  
Author(s):  
Bhawna Gupta ◽  
Tatiana S. Levchenko ◽  
Dmitry A. Mongayt ◽  
Vladimir P. Torchilin
Keyword(s):  
Monoclonal Antibody ◽  
Brain Tumor ◽  
Tumor Cells ◽  
Tumor Model ◽  
Subcutaneous Tumor ◽  
Brain Tumor Cells

scholarly journals The MEMIC: An ex vivo system to model the complexity of the tumor microenvironment

2021 ◽  
Author(s):  
Libuše Janská ◽  
Libi Anandi ◽  
Nell C. Kirchberger ◽  
Zoran S. Marinkovic ◽  
Logan T. Schachtner ◽  
...  
Keyword(s):  
Tumor Microenvironment ◽  
Tumor Cells ◽  
Ex Vivo ◽  
Tumor Stroma ◽  
Stem Cell Differentiation ◽  
Blood Stream ◽  
Direct Access ◽  
Ex Vivo Model

There is an urgent need for accurate, scalable, and cost-efficient experimental systems to model the complexity of the tumor microenvironment. Here, we detail how to fabricate and use the Metabolic Microenvironment Chamber (MEMIC) – a 3D-printed ex vivo model of intratumoral heterogeneity. A major driver of the cellular and molecular diversity in tumors is the accessibility to the blood stream that provides key resources such as oxygen and nutrients. While some tumor cells have direct access to these resources, many others must survive under progressively more ischemic environments as they reside further from the vasculature. The MEMIC is designed to simulate the differential access to nutrients and allows co-culturing different cell types, such as tumor and immune cells. This system is optimized for live imaging and other microscopy-based approaches, and it is a powerful tool to study tumor features such as the effect of nutrient scarcity on tumor-stroma interactions. Due to its adaptable design and full experimental control, the MEMIC provide insights into the tumor microenvironment that would be difficult to obtain via other methods. As a proof of principle, we show that cells sense gradual changes in metabolite concentration resulting in multicellular spatial patterns of signal activation and cell proliferation. To illustrate the ease of studying cell-cell interactions in the MEMIC, we show that ischemic macrophages reduce epithelial features in neighboring tumor cells. We propose the MEMIC as a complement to standard in vitro and in vivo experiments, diversifying the tools available to accurately model, perturb, and monitor the tumor microenvironment, as well as to understand how extracellular metabolites affect other processes such as wound healing and stem cell differentiation.

scholarly journals Breast Tumor Cells Highly Resistant to Drugs Are Controlled Only by the Immune Response Induced in an Immunocompetent Mouse Model

2019 ◽  
Vol 18 ◽  
pp. 153473541984804 ◽  
Author(s):  
Paola Lasso ◽  
Mónica Llano Murcia ◽  
Tito Alejandro Sandoval ◽  
Claudia Urueña ◽  
Alfonso Barreto ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Immune Response ◽  
Tumor Cells ◽  
High Capacity ◽  
Cancer Cell Line ◽  
Tumor Model ◽  
Main Element ◽  
In Vivo Models

Background: The tumor cells responsible for metastasis are highly resistant to chemotherapy and have characteristics of stem cells, with a high capacity for self-regeneration and the use of detoxifying mechanisms that participate in drug resistance. In vivo models of highly resistant cells allow us to evaluate the real impact of the immune response in the control of cancer. Materials and Methods: A tumor population derived from the 4T1 breast cancer cell line that was stable in vitro and highly aggressive in vivo was obtained, characterized, and determined to exhibit cancer stem cell (CSC) phenotypes (CD44+, CD24+, ALDH+, Oct4+, Nanog+, Sox2+, and high self-renewal capacity). Orthotopic transplantation of these cells allowed us to evaluate their in vivo susceptibility to chemo and immune responses induced after vaccination. Results: The immune response induced after vaccination with tumor cells treated with doxorubicin decreased the formation of tumors and macrometastasis in this model, which allowed us to confirm the immune response relevance in the control of highly chemotherapy-resistant ALDH+ CSCs in an aggressive tumor model in immunocompetent animals. Conclusions: The antitumor immune response was the main element capable of controlling tumor progression as well as metastasis in a highly chemotherapy-resistant aggressive breast cancer model.

Dendritic cells modified to express CD40 ligand elicit therapeutic immunity against preexisting murine tumors

Blood ◽  
2000 ◽  
Vol 96 (1) ◽  
pp. 91-99 ◽  
Author(s):  
Toshiaki Kikuchi ◽  
Malcolm A. S. Moore ◽  
Ronald G. Crystal
Keyword(s):  
Dendritic Cells ◽  
Cytotoxic T Lymphocyte ◽  
Tumor Regression ◽  
Ex Vivo ◽  
Tumor Model ◽  
Adenovirus Vector ◽  
Cd40 Ligand ◽  
Murine Tumors

CD40 ligand (CD40L) is essential for the initiation of antigen-specific T-cell responses. This study is based on the hypothesis that dendritic cells (DCs) genetically modified ex vivo to express CD40L will enhance in vivo presentation of tumor antigen to the cellular immune system with consequent induction of antitumor immunity to suppress tumor growth. To examine this concept, subcutaneous murine tumors were injected with bone marrow-derived DCs that had been modified in vitro with an adenovirus (Ad) vector expressing murine CD40L (AdmCD40L). In B16 (H-2b, melanoma) and CT26 (H-2d, colon cancer) murine models, intratumoral injection of 2 × 106 AdmCD40L-modified DCs (CD40L-DCs) to established (day 8) subcutaneous tumors resulted in sustained tumor regression and survival advantage. This antitumor effect was sustained when the number of CD40L-DCs were reduced 10-fold to 2 × 105. Analysis of spleens from CD40L-DC–treated animals demonstrated that CD40L-DCs injected into the subcutaneous CT26 flank tumors migrated to the spleen, resulting in activation of immune-relevant processes. Consistent with this concept, intratumoral administration of CD40L-DCs elicited tumor-specific cytotoxic T-lymphocyte responses, and the transfer of spleen cells from CD40L-DC–treated mice efficiently protected naive mice against a subsequent tumor challenge. In a distant 2-tumor model of metastatic disease, an untreated B16 tumor in the right flank regressed in parallel with a left B16 tumor treated with direct injection of CD40L-DCs. These results support the concept that genetic modification of DCs with a recombinant CD40L adenovirus vector may be a useful strategy for directly activating DCs for cancer immunotherapy.

scholarly journals Anti-Tumoral and Anti-Angiogenic Effects of Low-Diluted Phenacetinum on Melanoma

2021 ◽  
Vol 11 ◽  
Author(s):  
Camille Fuselier ◽  
Sandrine Quemener ◽  
Eleonore Dufay ◽  
Camille Bour ◽  
Camille Boulagnon-Rombi ◽  
...  
Keyword(s):  
Endothelial Cells ◽  
Side Effects ◽  
Ex Vivo ◽  
Tumor Model ◽  
Primary Cutaneous Melanoma ◽  
Relieve Pain ◽  
Melanoma Treatment ◽  
Vertical Growth Phase

Melanoma is the most aggressive form of skin cancer and the most rapidly expanding cancer in terms of worldwide incidence. If primary cutaneous melanoma is mostly treated with a curative wide local excision, malignant melanoma has a poor prognosis and needs other therapeutic approaches. Angiogenesis is a normal physiological process essential in growth and development, but it also plays a crucial role in crossing from benign to advanced state in cancer. In melanoma progression, angiogenesis is widely involved during the vertical growth phase. Currently, no anti-angiogenic agents are efficient on their own, and combination of treatments will probably be the key to success. In the past, phenacetin was used as an analgesic to relieve pain, causing side effects at large dose and tumor-inducing in humans and animals. By contrast, Phenacetinum low-dilution is often used in skin febrile exanthema, patches profusely scattered on limbs, headache, or flushed face without side effects. Herein are described the in vitro, in vivo, and ex vivo anti-angiogenic and anti-tumoral potentials of Phenacetinum low-dilution in a B16F1 tumor model and endothelial cells. We demonstrate that low-diluted Phenacetinum inhibits in vivo tumor growth and tumor vascularization and thus increases the survival time of B16F1 melanoma induced-C57BL/6 mice. Moreover, Phenacetinum modulates the lung metastasis in a B16F10 induced model. Ex vivo and in vitro, we evidence that low-diluted Phenacetinum inhibits the migration and the recruitment of endothelial cells and leads to an imbalance in the pro-tumoral macrophages and to a structural malformation of the vascular network. All together these results demonstrate highly hopeful anti-tumoral, anti-metastatic, and anti-angiogenic effects of Phenacetinum low-dilution on melanoma. Continued studies are needed to preclinically validate Phenacetinum low-dilution as a complementary or therapeutic strategy for melanoma treatment.

scholarly journals Modification of a Popular Syngeneic Murine Mammary Tumor Model for Immunotherapy Studies

2011 ◽  
Vol 2011 ◽  
pp. 1-8 ◽  
Author(s):  
Armando Rivera ◽  
Xinping Fu ◽  
Lihua Tao ◽  
Xiaoliu Zhang
Keyword(s):  
Tumor Antigen ◽  
Growth Pattern ◽  
Cytotoxic T Cells ◽  
Growth Factor Receptor ◽  
Tumor Model ◽  
Parental Line ◽  
Mammary Tumor Model ◽  
4T1 Breast Cancer

To facilitate the evaluation of immunotherapeutic intervention against malignant diseases, it is desirable to have a syngeneic tumor model that closely resembles the growth pattern of human tumors. Murine 4T1 breast cancer model is known for its metastatic properties that mimic its human counterpart. However, a drawback of this model is the lack of an identified tumor antigen to function as a therapeutic target for immunologic intervention. We used the piggyBac transposon system to stably transduce a tumor antigen, the human epidermal growth factor receptor 2 gene (HER2), into this tumor cell. In vitro characterization shows that the newly established cells have a similar growth pattern as the parental line. In vivo evaluation shows that host immune response was generated against the HER2 tumor antigen, despite the high homology between HER2 and its murine counterpart (neu gene). When implanted into immune-deficient mice, the HER2-expressing 4T1 cells readily formed sizable tumors, indicating that these cells are useful for evaluating the therapeutic effect of adoptively transferred cytotoxic T cells that are specifically raised or modified to target the HER2 tumor antigen.

scholarly journals A Polysaccharide From the Whole Plant of Plantago asiatica L. Enhances the Antitumor Activity of Dendritic Cell-Based Immunotherapy Against Breast Cancer

2021 ◽  
Vol 12 ◽  
Author(s):  
Jiafeng Gao ◽  
Yi-Nan Zhang ◽  
Jingwen Cui ◽  
Jiatong Zhang ◽  
Yuexiang Ming ◽  
...  
Keyword(s):  
Breast Cancer ◽  
T Cells ◽  
Breast Tumor ◽  
Cytotoxic T Cells ◽  
Tumor Model ◽  
Whole Plant ◽  
Plantago Asiatica ◽  
Breast Tumor Model

Dendritic cells (DCs) are the most potent professional antigen-presenting cells (APCs) that mediate T-cell immune responses. Breast cancer is one of the most commonly diagnosed diseases and its mortality rate is higher than any other cancer in both humans and canines. Plantain polysaccharide (PLP), extracted from the whole plant of Plantago asiatica L., could promote the maturation of DCs. In this research, we found that PLP could upregulate the maturation of DCs both in vitro and in vivo. PLP-activated DCs could stimulate lymphocytes’ proliferation and differentiate naive T cells into cytotoxic T cells. Tumor antigen-specific lymphocyte responses were enhanced by PLP and CIPp canine breast tumor cells lysate-pulsed DCs, and PLP and CIPp-cell-lysate jointly stimulated DCs cocultured with lymphocytes having the great cytotoxicity on CIPp cells. In the 4T1 murine breast tumor model, PLP could control the size of breast tumors and improve immunity by recruiting DCs, macrophages, and CD4+ and CD8+ T cells in the tumor microenvironment. These results indicated that PLP could achieve immunotherapeutic effects and improve immunity in the breast tumor model.

Induction of a long-lasting antitumor immunity by a trifunctional bispecific antibody

Blood ◽  
2001 ◽  
Vol 98 (8) ◽  
pp. 2526-2534 ◽  
Author(s):  
Peter Ruf ◽  
Horst Lindhofer
Keyword(s):  
Tumor Cell ◽  
Tumor Cells ◽  
Antitumor Immunity ◽  
Residual Disease ◽  
B Cell Lymphoma ◽  
Disseminated Tumor Cells ◽  
Cell Killing ◽  
Tumor Cell Killing

Abstract Bispecific antibodies (bsAbs) can efficiently mediate tumor cell killing by redirecting preactivated or costimulated T cells to disseminated tumor cells, especially in a minimal residual disease situation. This study demonstrates that the trifunctional bsAb BiLu is able to kill tumor cells very efficiently without any additional costimulation of effector cells in vitro and in vivo. Remarkably, this bsAb also induces a long-lasting protective immunity against the targeted syngeneic mouse tumors (B16 melanoma and A20 B-cell lymphoma, respectively). A strong correlation was observed between the induction of a humoral immune response with tumor-reactive antibodies and the survival of mice. This humoral response was at least in part tumor specific as shown in the A20 model by the detection of induced anti-idiotype antibodies. Both the survival of mice and antitumor titers were significantly diminished when F(ab′)2 fragments of the same bsAb were applied, demonstrating the importance of the Fc region in this process. With the use of T-cell depletion, a contribution of a cellular antitumor response could be demonstrated. These results reveal the necessity of the Fc region of the bsAb with its potent immunoglobulin subclass combination mouse immunoglobulin G2a (IgG2a) and rat IgG2b. The antigen-presenting system seems to be crucial for achieving an efficient tumor cell killing and induction of long-lasting antitumor immunity. Hereby, the recruitment and activation of accessory cells by the intact bsAb is essential.

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