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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.
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.
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.
Stereotactic body radiation therapy (SBRT) has emerged as an important innovative treatment for various primary and metastatic cancers. This book provides a comprehensive and up-to-date account of the physical/technological, biological, and clinical aspects of SBRT. It will serve as a detailed resource for this rapidly developing treatment modality. The organ sites covered include lung, liver, spine, pancreas, prostate, adrenal, head and neck, and female reproductive tract. Retrospective studies and prospective clinical trials on SBRT for various organ sites from around the world are examined, and toxicities and normal tissue constraints are discussed. This book features unique insights from world-renowned experts in SBRT from North America, Asia, and Europe. It will be necessary reading for radiation oncologists, radiation oncology residents and fellows, medical physicists, medical physics residents, medical oncologists, surgical oncologists, and cancer scientists.
Intensity-modulated radiation therapy (IMRT), one of the most important developments in radiation oncology in the past 25 years, involves technology to deliver radiation to tumors in the right location, quantity and time. Unavoidable irradiation of surrounding normal tissues is distributed so as to preserve their function. The achievements and future directions in the field are grouped in the three sections of the book, each suitable for supporting a teaching course. Part 1 contains topical reviews of the basic principles of IMRT, part 2 describes advanced techniques such as image-guided and biologically based approaches, and part 3 focuses on investigation of IMRT to improve outcome at various cancer sites.
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.
We previously demonstrated that radiation therapy (RT) and hormone therapy (HT) induce tumor-specific autoantibody responses in human prostate cancer and this grant is investigating the clinical significance of these findings. In Aim 1 the Shionogi mouse tumor model is being used to study the effect of HT and RT induced immune responses on tumor recurrence. In the past year we have shown that HT induces autoantibody and T cell responses against the tumor antigen Poly A Binding Protein (PABP) in this model. Contrary to our hypothesis these immune responses are associated with earlier tumor recurrence which underscores the importance of performing analogous studies in human prostate cancer patients (Aims 2 and 3). To this end we have established a platform for testing human T cell responses against serologically-defined tumor antigens and we have collected large blood samples from prostate cancer patients showing treatment-induced autoantibody responses (Aim 2). We have also started to assemble cohorts of prostate cancer patients with recurrent versus non-recurrent disease at 5 years post-treatment (Aim 3). In summary this study is progressing on schedule and is revealing unexpected results that we believe may be highly relevant to prognosis and treatment of prostate cancer.
Here, we propose to harness the immune system by immunotherapy (IT) alongside conventional radiotherapy (RT) to improve the treatment of men with advanced or recurrent prostate cancer. The overall aim is to determine whether local irradiation of prostate tumors in a preclinical and clinical setting leads to measurable tumor-specific immune responses and whether tumor vaccination can boost these immune responses possibly leading to better tumor control. Survivin is our tumor antigen of choice because it seems superior to other prostate tumor antigens. We generated stable mouse prostate cancer cell lines (TRAMP C1 and TRAMP C2) that express human HLA-A2.1 and we were able to confirm that these cells express survivin. These are two important steps as this will allow us to examine the responses to human surviving epitopes that are clinically relevant within a transgenic humanized mouse model. Enumeration of circulating survivin-specific CD8+ T lymphocytes in prostate cancer patients using tetramers indicated that many patients have higher than normal numbers of these T cells and that they are increased further upon completion of radiation treatment. Whether or not this is due to increase in antigenic peptide liberation and whether this will translate to tumor regression we don't know. What is clear is that RT does not induce immune tolerance to surviving making IT approaches feasible in combination with RT.