Escape strategies and reasons for failure in the interaction between tumour cells and the immune system: how can we tilt the balance towards immune-mediated cancer control?
ABSTRACT The last decade has witnessed an exponential increase in the attempts to demonstrate that adaptive immunity can effectively detect cancer cells and impair their growth in vivo in cancer patients. However, clinical trials of immunotherapy with a broad array of immunisation strategies have depicted a rather disappointing scenario, suggesting that successful control of tumour growth by immunotherapeutic treatments may not be an easy task to achieve. The attention of tumour immunologists has thus been switched to the potential reasons of failure, and extensive efforts are being made in defining the cellular and molecular pathways interfering with the capacity of the immune system to develop powerful immunological reactions against tumour cells. Although many of these pathways have been well characterised in murine models, little and controversial information about their role in determining neoplastic progression in cancer patients is available. This discrepancy at the moment represents one of the major limitations in understanding the obstacles to the in vivo development of protective T cell-mediated immune responses against tumours, and how pharmacological or biological interventions aimed at bypassing tumour escape mechanisms would indeed result in a clinical benefit. The study of the reasons for the failure of the immune system to control tumour growth, which have to be ascribed to highly interconnected phenomena occurring at both tumour and immune levels, could in the near future provide adequate tools to fight cancer by finely tuning the host environment through biological therapies.
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ABSTRACT: CD47 is a "self marker" that is usually overexpressed on the surface of cancer cells to enable them to escape immunosurveillance. Recognition of CD47 by its receptor, signal regulatory protein α (SIRPα), which is expressed in the macrophages, inhibits phagocytic destruction of cancer cells by the macrophages. In this study, we have first shown that clinical isolates of human melanoma significantly upregulate CD47, possibly as a mechanism to defend themselves against the macrophages. We then exploited RNA interference (RNAi) technology to test the hypothesis that knocking down CD47 in the tumor cells will render them targets for macrophage destruction; hence, creating a novel anti-cancer therapy. Anti-CD47 siRNA was encapsulated in a liposome-protamine-hyaluronic acid (LPH) nanoparticle (NP) formulation to address the challenge of targeted delivery of siRNA-based therapeutics in vivo. Efficient silencing of CD47 in tumor tissues with systemic administration of LPH(CD47) also significantly inhibited the growth of melanoma tumors. In a lung metastasis model, LPH(CD47) efficiently inhibited lung metastasis to about 27% of the untreated control. Moreover, no hematopoietic toxicity was observed in the animals that received multiple doses of LPH(CD47). Our findings indicate CD47 as a potential prognostic marker for melanoma development as well as a target for therapeutic intervention with RNAi-based nanomedicines.Molecular Therapy (2013); doi:10.1038/mt.2013.135.Molecular Therapy 06/2013; · 6.43 Impact Factor
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ABSTRACT: We review recent advances leading to a new understanding of immunology of breast cancer with its potential clinical applications. With the exception of antibody-based HER2 targeting, immunotherapy in breast cancer has largely been an unsatisfying experience. To improve the efficacy of breast cancer immunotherapeutics, a better understanding of the relation between innate and adaptive immune responses, of the immune escape mechanisms, the discovery of mechanisms underlying immunological tolerance, and the acknowledgment of the importance of both cell-mediated and humoral adaptive immunity for the control of tumor growth are needed. Cancer takes advantage of the ability to hide from the immune system by exploiting a series of immune escape mechanisms. Among these mechanisms are the hijackings of immune cell-intrinsic checkpoints that are induced on T-cell activation. Blockade of these checkpoints - cytotoxic T-lymphocyte-associated antigen 4 or the programmed death 1 receptor - recently provided the first evidence of activity of an immune-modulation approach in the treatment of solid tumors. The future frontier in the immunotherapeutics of breast cancer requires identification of predictive factors. The immune system remembers what it targets, so once the system is correctly activated, it may mediate a long-lasting tumor response.Current opinion in oncology 09/2013; · 3.76 Impact Factor
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ABSTRACT: Ret transgenic mouse model of skin malignant melanoma is characterized by the overexpression of the human ret transgene in melanin containing cells. Transgenic mice spontaneously develop skin tumors with metastases in lymph nodes, lungs, liver, brain, and the bone marrow. Tumor lesions show typical melanoma morphology and express melanoma-associated antigens. Although transgenic mice demonstrate an accumulation of melanoma antigen-specific memory and effector T cells, their anti-tumor effects could be blocked by highly immunosuppressive leukocytes enriched in the tumor microenvironment and in the periphery. Here we discus the role of one of the most potent immunosuppressive subset, regulatory T cells, in the melanoma progression in this model. This article is protected by copyright. All rights reserved.Pigment Cell & Melanoma Research 04/2013; · 5.84 Impact Factor