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Radiotherapy is generally considered to be immunosuppressive, whereas we hypothesized that it modulates immune responses and has profound effects on the immune system rather than eliminating of lymphocytes. The goal of this study was to determine how radiation affects the presentation of prostate specific antigen (PSA), to investigate new potential mechanisms of altered immune function after radiation therapy, and to devise strategies to overcome radiation-induced immunosuppression in prostate cancer using treatment with IL-3 and/or GM-CSF. In addition, because of the high risk nature of the experiments and the high PSA expression levels in prostate cancer patients that might interfere with its efficacy, we developed a second model using survivin as an antigen, since it also is over-expressed in prostate and other cancers.
Numerous developments in molecular biology have led to an explosive growth in the knowledge underlying mechanisms of carcinogenesis, cell signalling, tumor progression and development of metastasis. However, cure of cancer is still hampered by the inherited capacity of tumors to become resistant to standard therapies, to metastasize from their initial location and to proliferate in other tissue compartments. Radiotherapy is one of the main treatment modalities to achieve locoregional tumor control. However, the treatment of distant metastases further remains to be a challenge. In this special topic we are interested to elucidate immunological aspects which are initiated and affected by radiotherapy. We also aim to describe the development of innovative immunological strategies from a preclinical stage to clinical application which could be combined with standard radiotherapeutic approaches. A special interest will also deal with the effects of radiotherapy on tumor initiating cells as well as on the tumor microenvironment. Last but not least the effects of different irradiation sources and qualities such as photones, protones and heavy ions will be analyzed with respect to immunological outcome.
In this book, leading experts in cancer immunotherapy join forces to provide a comprehensive guide that sets out the main principles of oncoimmunology and examines the latest advances and their implications for clinical practice, focusing in particular on drugs with FDA/EMA approvals and breakthrough status. The aim is to deliver a landmark educational tool that will serve as the definitive reference for MD and PhD students while also meeting the needs of established researchers and healthcare professionals. Immunotherapy-based approaches are now inducing long-lasting clinical responses across multiple histological types of neoplasia, in previously difficult-to-treat metastatic cancers. The future challenges for oncologists are to understand and exploit the cellular and molecular components of complex immune networks, to optimize combinatorial regimens, to avoid immune-related side effects, and to plan immunomonitoring studies for biomarker discovery. The editors hope that this book will guide future and established health professionals toward the effective application of cancer immunology and immunotherapy and contribute significantly to further progress in the field.
Advances in Cancer Research, Volume 150, the latest release in this ongoing series, covers the relationship(s) between autophagy and senescence, how they are defined, and the influence of these cellular responses on tumor dormancy and disease recurrence. Specific sections in this new release include Autophagy and senescence, converging roles in pathophysiology, Cellular senescence and tumor promotion: role of the unfolded protein response, autophagy and senescence in cancer stem cells, Targeting the stress support network regulated by autophagy and senescence for cancer treatment, Autophagy and PTEN in DNA damage-induced senescence, mTOR as a senescence manipulation target: A forked road, and more. Addresses the relationship between autophagy and senescence in cancer therapy Covers autophagy and senescence in tumor dormancy Explores autophagy and senescence in disease recurrence
For long, high dose ionizing radiation was considered as a net immune suppressing agent, as shown, among others, by the exquisite radiosensitivity of the lymphoid system to radiation-induced cell killing. However, recent advances in radiobiology and immunology have made this picture more complex. For example, the recognition that radiation-induced bystander effects, share common mediators with various immunological signalling processes, suggests that they are at least partly immune mediated. Another milestone was the finding, in the field of onco-immunology, that local tumor irradiation can modulate the immunogenicity of tumor cells and the anti-tumor immune responsiveness both locally, in the tumor microenvironment, and at systemic level. These observations paved the way for studies exploring optimal combinations of radiotherapy and immunotherapy in order to achieve a synergistic effect to eradicate tumors. However, not all interactions between radiation and the immune system are beneficial, as it was recognized that many of radiation-induced late side effects are also of immune and inflammatory nature. Currently perhaps the most studied field of research in radiation biology is focused around the biological effects of low doses, where many of the observed pathophysiological endpoints are due to mechanisms other than direct radiation-induced cell killing and are immune-related. Finally, it must not be forgotten that the interactions between the ionizing radiations and the immune system are bi-directional, and activation of the immune system also influences the outcome of radiation exposure. This Research Topic brings together 23 articles and aims to give an overview of the complex and very often contradictory nature of the interactions between ionizing radiation and the immune system. Due to its increasing penetrance in the population both through medical diagnostic or environmental sources or during cosmic travel low dose ionizing radiation exposure is becoming a major epidemiological concern world-wide. Several of the articles within the Research Topic specifically address potential long-term health consequences and the underlying mechanisms of low dose radiation exposure. A major intention of the Editors was also to draw the attention of the non-radiobiological scientific community on the fact that ionizing radiation is by far more than purely an immune suppressing agent.
This book overviews cancer immunity from broad scientific fields, based on the concept that cancer is a sort of by-product of infection, inflammation, and host immune response. The innate and acquired arms of the immune system mainly participate in tumor immune surveillance, and their activation is critically modulated by the situation of the tumor microenvironment. Many types of immune cells join the formation of the microenvironment. In particular, macrophages and dendritic cells enter the tumor mass to be main players in the inflammatory milieu of tumors. After introducing these topics, the book discusses immunotherapy for cancer patients as an outgrowth of this concept of infection and inflammation. With the contributions of leading scientists actively involved in the field of antitumor immunity study, this book encourages readers to understand the mechanism of general cancers based on inflammation and will facilitate prevention and the development of therapeutics for cancer.
Radiation therapy (RT) is the front line treatment for prostate cancer in the early stages but is relatively ineffective against large tumor volumes and it is difficult to use it against micrometastatic disease. Immunotherapy (IT) has become popular as an alternative treatment since the discovery of prostate tumor-associated antigens (TAA) and of corresponding tumor-specific T cells in prostate cancer patients. However, IT is not a very effective modality on its own due to multiple tumor escape mechanisms and probably would benefit from combination with other therapies, such as RT. At least in theory, a potential advantage is that radiation affects the immune system by upregulating MHC class I and co-stimulatory molecules, which could promote T cell filtration into tumors and T cell activation. On the other hand, we recently showed that radiation affects proteasome function, which could affect antigen processing, and appears to have other effects on DC antigen presentation. In the first year of this study, we have been constructing cell lines to examine this in prostate cancer. We have also examined the effects of radiation on DC processing PSA either endogenously or exogenously as well as on proteasome and immunoproteasome function in DCs. The final goal of the proposal is to determine if radiation affects the hierarchy of antigenic peptide presented by DCs and tumor cells and to devise better strategies in combination treatments of RT and IT.
Modern medical imaging and radiation therapy technologies are so complex and computer driven that it is difficult for physicians and technologists to know exactly what is happening at the point-of-care. Medical physicists responsible for filling this gap in knowledge must stay abreast of the latest advances at the intersection of medical imaging an
The major goal of the project is to investigate the radiosensitization activity and mechanism of action of novel IAP-inhibitors in prostate cancer. We have investigated the in vitro radiosensitization activity of our lead IAP-inhibitors, SH-130 and Embelin, in human prostate cancer cell lines. IAP-inhibitors potently enhanced TRAIL-/radiation-induced apoptosis and growth inhibition. Using NMR and Crystal Structure Analysis, we conclusively show that these IAP inhibitors bind to the pocket in the XIAP BIR3 domain where Smac binds. Biotin-labeled SH-130 pull-down assay further confirm that BIR3 domain in XIAP and cIAP-1 is indeed the molecular target of the IAP inhibitors in apoptosis-potentiation. Based on our exciting data obtained from this PCRP project, together with data from other collaborators, we are working with FDA for ND filing aiming for Phase I clinical trial with SH-130 as radiosensitizer for prostate cancer.