Rivoltini, L, Canese, P, Huber, V, Iero, M, Pilla, L, Valenti, R et al.. 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? Expert Opin Biol Ther 5: 463-476
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.
- "The identification of immunological and genetic features affecting immune response in patients with minimal tumor burden represents the optimal background for development of clinical studies in the adjuvant setting as it should allow the immune system to mount a response before it is overtaken. An active immunization may provide a non-toxic therapeutic modality able to induce anti-tumor immune responses in patients with cancer . However, the majority of the trials so far have been conducted in the metastatic setting, which could have significantly impacted the results because of the large tumor burden [52-56]. "
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ABSTRACT: Immunotherapy for the treatment of breast cancer can be categorized as either (a) specific stimulation of the immune system by active immunization, with cancer vaccines, or (b) passive immunization, such as tumor-specific antibodies (including immune modulators) or adoptive cell therapy that inhibit the function of, or directly kill, tumor cells. We will present the current information and the future perspectives of immunotherapy in patients with breast cancer, including the prognostic role of tumor infiltrating lymphocytes, immune signatures, targeted therapies modulating the immune system, and tumor antigen cancer vaccines. Active immunotherapy in breast cancer and its implementation into clinical trials have been largely a frustrating experience in the last decades. The concept that the immune system regulates cancer development is experiencing a new era of interest. It is clear that the cancer immunosurveillance process indeed exists and potentially acts as an extrinsic tumor suppressor. Also, the immune system can facilitate tumor progression by sculpting the immunogenic phenotype of tumors as they develop. Cancer immunoediting represents a refinement of the cancer immunosurveillance hypothesis and resumes the complex interaction between tumor and immune system into three phases: elimination, equilibrium, and escape. Major topics in the field of immunology deserve a response: what do we know about tumor immunogenicity, and how might we therapeutically improve tumor immunogenicity? How can we modulate response of the immune system? Is there any gene signature predictive of response to immune modulators? The success of future immunotherapy strategies will depend on the identification of additional immunogenic antigens that can serve as the best tumor-rejection targets. Therapeutic success will depend on developing the best antigen delivery systems and on the elucidation of the entire network of immune signaling pathways that regulate immune responses in the tumor microenvironment.
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- "Several mechanisms have reported may contribute to the ability of tumor cells to survive in the context of an active immune response, including inhibition of cytotoxic activity by secretion of unique factors (Kim et al., 2007), systematically inhibition of immune response by upregulation of inhibitory cytokines such as interleukin 10 (IL-10) (Yang et al., 2003), or escaping immune destruction by down-regulation of the expression of MHC molecules on the surface of tumor cells (Igney et al., 2002; Rivoltini et al., 2005). Exosomes are small membrane vesicles found in cell culture supernatants and in different biological fluids. "
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Brain tumors almost universally have fatal outcomes; new therapeutics are desperately needed and will only come from improved understandins of glioma biology.
Exosomes are endosomally derived 30~100 nm membranous vesicles released from many cell types. Examples from GL26 cells were here purified using density gradient ultracentrifugation and monitored for effects on GL26 tumor growth in C57BL/6j mice (H-2b). Lactate dehydrogenase release assays were used to detect the cytotoxic activity of CD8+T and NK cells. Percentages of immune cells producing intracellular cytokines were analyzed by FACS.
In this study, exosomes from murine-derived GL26 cells significantly promoted in vivo tumor growth in GL26-bearing B6 mice. Then we further analyzed the effects of the GL26 cells-derived exosomes on immune cells including CD8+T, CD4+T and NK cells. Inhibition of CD8+T cell cytotoxic activity was demonstrated by CD8+T cell depletion assays in vivo and LDH release assays in vitro. The treatment of mice with exosomes also led to a reduction in the percentages of CD8+T cells in splenocytes as determined by FACS analysis. Key features of CD8+T cell activity were inhibited, including release of IFN-gamma and granzyme B. There were no effects of exosomes on CD4+T cells and NK cells.
Based on our data, for the first time we demonstrated that exosomes from murine derived GL26 cells promote the tumor growth by inhibition of CD8+T cells in vivo and thus may be a potential therapeutic target.
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- "These paradoxical results of clinical trials in malignant melanoma seem to be due to the intensive immunosuppression mediated by different mechanisms dealing with structural and functional changes both in tumor and stroma cells. These mechanisms were reported to include on the side of melanoma cells (i) the absence of co-stimulatory molecules , (ii) a down regulation in the expression of tumor associated antigens , (iii) MHC class I molecules , and (iv) ligands for natural killer cell receptors , as well as (v) an intensive secretion of immunosuppressive factors such as vascular endothelial growth factor (VEGF), transforming growth factor (TGF)-␤, interleukin (IL)-10, nitric oxide (NO) or prostaglandins  . The contribution of stroma cells in the observed immune escape has been characterized by a strong recruitment, expansion and accumulation of immunosuppressive cells in the tumor microenvironment such as CD4 + CD25 + Foxp3 + regulatory T cells  , myeloid-derived suppressor cells (MDSCs)  , tumor-associated macrophages (TAMs)  , Tie2-expressing monocytes (TEMs) , N2 polarized subset of neutrophils  , and regulatory/tolerogenic dendritic cells (DCs) . "
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ABSTRACT: Malignant melanoma is characterized by a rapid progression, metastasis to distant organs, and resistance to chemo- and radiotherapy. Well-defined immunogenic capacities of melanoma cells should allow a successful application of different immunotherapeutic strategies. However, the overall results of immunotherapeutic clinical studies are not satisfactory. These paradoxical observations are supposed to be due to the profound immunosuppression mediated by different mechanisms dealing with alterations in tumor and surrounding stroma cells. Melanoma microenvironment has been characterized by a remarkable accumulation of highly immunosuppressive regulatory leucocytes, in particular, myeloid-derived suppressor cells (MDSCs). Their migration, retention and high activity in the tumor lesions have been demonstrated to be induced by chronic inflammatory conditions developing in the tumor microenvironment and characterized by the long-term secretion of various inflammatory mediators (cytokines, chemokines, growth factors, reactive oxygen and nitrogen species, prostaglandins etc.) leading to further cancer progression. Here, we discuss the role of chronic inflammation in the recruitment and activation of MDSCs in melanoma lesions as well as therapeutic approaches of MDSC targeting to overcome tumor immunosuppressive microenvironment induced by chronic inflammation and enhance the efficiency of melanoma immunotherapies.
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