Immunosuppressive Strategies that are Mediated by Tumor Cells

Division of Immunogenetics, Hospital de Clínicas José de San Martín, University of Buenos Aires, Buenos Aires, Argentina.
Annual Review of Immunology (Impact Factor: 39.33). 02/2007; 25(1):267-96. DOI: 10.1146/annurev.immunol.25.022106.141609
Source: PubMed


Despite major advances in understanding the mechanisms leading to tumor immunity, a number of obstacles hinder the successful translation of mechanistic insights into effective tumor immunotherapy. Such obstacles include the ability of tumors to foster a tolerant microenvironment and the activation of a plethora of immunosuppressive mechanisms, which may act in concert to counteract effective immune responses. Here we discuss different strategies employed by tumors to thwart immune responses, including tumor-induced impairment of antigen presentation, the activation of negative costimulatory signals, and the elaboration of immunosuppressive factors. In addition, we underscore the influence of regulatory cell populations that may contribute to this immunosuppressive network; these include regulatory T cells, natural killer T cells, and distinct subsets of immature and mature dendritic cells. The current wealth of preclinical information promises a future scenario in which the synchronized blockade of immunosuppressive mechanisms may be effective in combination with other conventional strategies to overcome immunological tolerance and promote tumor regression.

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Available from: Eduardo M Sotomayor, Feb 21, 2014
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    • "In addition to sense the presence of exogenous antigens, immune system is also able to recognize the tumor-associated antigens and eliminate the neoplastic cells-a process called immunosurveillance [4]. Tumor cells proliferate in an immunosuppressive microenvironment, which renders their efficient clearance by the immune system inefficient [5]. DCs, owing to their excellent capacity for antigen-presentation and T-cell stimulation, have been considered as potential candidates for immunotherapy. "

    Full-text · Article · Dec 2015
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    • "The two-way interactions between DCs and T cells initiate either an immunogenic or a tolerogenic pathway, both of which can play crucial roles in tumor immunity[62]. Tumors can mimic some of the signaling pathways of the immune system, thus propagating conditions that favor immune tolerance and escaping tumor immunity[63]. It has been shown, here and in other reports, that CRC cells can confer tolerogenic behavior on MoDCs by inducing phenotypic alterations and reducing the ability to stimulate T cells. "
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    ABSTRACT: Dendritic cells (DCs), specialized antigen-presenting cells bridging innate and adaptive immunity, play a crucial role in determining specific immune response to tumors. Because of their potent immunoregulatory capacities, DCs have been exploited in anticancer vaccination, with limited success thus far. This pilot study compared low-dose interleukin (IL)-4 and IL-12 prepared by sequential kinetic activation (SKA) with standard doses of the same recombinant human cytokines on functional activity of ex vivo-generated monocyte-derived (Mo) DCs from colon carcinoma patients and normal subjects. MoDCs were exposed to medium alone, SKA-IL-4 (0.5 fg/ml), or SKA-IL-12 (2 fg/ml), alone or consecutively combined, in parallel with rhIL-4 (50 ng/ml) and rhIL-12 (1 ng/ml). Primary allogeneic one-way mixed lymphocyte reaction (MLR) was the end point to assess in vitro T-lymphocyte proliferation in response to MoDCs, and secreted IL-12p70 and interferon-γ in MLR supernatants measured by ELISA to assay for T-helper 1-promoting MoDC phenotype. No single agent enhanced the compromised allostimulatory activity of MoDCs from colon cancer patients, unlike healthy donors. However, MoDCs from nonmetastatic colon cancer patients, after sequential exposure to SKA-IL-4 (48 hours) and SKA-IL-12 (24 hours), displayed increased T-cell stimulatory capacity by MLR and acquired driving T-helper 1 polarization activity, although less markedly than the effects induced by recombinant human cytokines or found in normal subjects. These results point to an immunomodulatory capacity of low-dose SKA-IL-4 and SKA-IL-12 and encourage further investigation to provide clues for the rational development of new and more effective immunotherapeutic strategies against cancer. Copyright © 2015 The Authors. Published by Elsevier Inc. All rights reserved.
    Full-text · Article · Aug 2015 · Translational oncology
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    • "Passive and active immunotherapy has been successfully applied to the treatment of a wide variety of human cancers [8] and holds promise of a lifelong cure [9]. However, tumor-induced immunosuppression still represents a major obstacle to effective cell-mediated immunity and immunotherapy [3] [5]. Accordingly, more insights into the main mechanisms associated with immune responses based on tumor specific features are required to obtain successful therapeutic outcomes with immunomodulatory strategies. "
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    ABSTRACT: Despite recent advances in the field of Oncoimmunology, the success potential of immunomodulatory therapies against cancer remains to be elucidated. One of the reasons is the lack of understanding on the complex interplay between tumor growth dynamics and the associated immune system responses. Towards this goal, we consider a mathematical model of vascularized tumor growth and the corresponding effector cell recruitment dynamics. Bifurcation analysis allows for the exploration of model's dynamic behavior and the determination of these parameter regimes that result in immune-mediated tumor control. Here, we focus on a particular tumor evasion regime that involves tumor and effector cell concentration oscillations of slowly increasing and decreasing amplitude, respectively. Considering a temporal multiscale analysis, we derive an analytically tractable mapping of model solutions onto a weakly negatively damped harmonic oscillator. Based on our analysis, we propose a theory-driven intervention strategy involving immunostimulating and immunosuppressive phases to induce long-term tumor control.
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