Pancreatic cancer is still one of the most lethal cancers with very unfortunate prognosis. The mortality rate follows closely the incidence rate. It ranks 9th in incidence but 4th in cancer related death , leaving the patients at first diagnosis with an overall median survival of 6-10 month. So far, surgery is the only chance of cure in this devastating disease . However, intended curative surgery is possible in about 20% only and even these patients have a median survival expectancy of less than two years .
Unfortunately, many treatment studies including surgery, chemotherapy and conventional radiotherapy have shown little progress in improving the prognosis of pancreatic cancer patients in the last decades. Therefore, novel alternatives such as therapies that alter the immune response are of high interest in this type of cancer. This is even more the case, since in pancreatic cancer several ways warding off spontaneously induced immune responses have been described : The aggressive nature of pancreatic ductal carcinoma is partially due to its tumor microenvironment with stellate cells producing the typical excessive desmoplasia [5, 6]. It has been shown in experimental cancer models in nude mice that tumors grew faster when pancreatic cancer cells and stellate cells were injected together . Stellate cells can support growth, invasion, metastasis and chemoresistance of tumors. Furthermore through recruitment and activation of stroma cell populations, pancreatic cancers generate a predominantly immune -suppressive microenvironment 
T-cell responses are partially regulated by dendritic cells, which take up antigens. Dendritic cells present the antigens to naïve T-cells and thereby activate them. Cytokines like type 1 interferon and extracellular matrix degregation products enhance dendritic cell activation, while IL-10 and TGF-β1 inhibit dendritic cell activation. In pancreatic cancer IL-10 and TGF-β1 are produced by stellate cells, cancer infiltrating macrophages and mast cells or regulatory T-cells [9, 10]. IL-10 and TGF-β1 can also be upregulated by irradiation e.g. in endothelial cells .
In pancreatic cancer MHC molecules and the Fas-receptor are downregulated making the cells more resistant to recognition and lysis by activated T-cells. Conversely, ionizing radiation has been shown to upregulate MHC molecules and Fas-receptors in vivo .
Gastrointestinal tumours, including pancreatic cancer induce, attract and maintain regulatory T-cells, which inhibit effector T-cells activation and function [13, 14]. Regulatory T cells and effector T-cells exhibit differences in their radiosensitivity  which opens a dose window for radiation induced immunotherapy.
Radiotherapy is a substantial part in the multimodal treatment of many solid cancers. The general understanding of the biology of radiation has been dominated by mitotic-catastrophic or apoptotic cell death. In addition to the classical effects such as DNA damage radiation also affects most other cell signaling circuits including MiRNA  which affects both the tumor cell and normal cell compartments with all aspects of the tumor microenvironment . Although radiation treatment has been known to be immunosuppressive, there is emerging evidence, that the effectiveness of radiation therapy can in part be due to its immunostimulating consequences [18, 19].
Potential mechanisms leading to immune response for ionizing radiation involve activation of stress response pathways e.g. activation of p53 and NF-κB. These abd others can regulate expression of molecules that promote a proinflammatory immune response including TNF-α, Interleukin-1 (IL-1), ICAM-1, VCAM-1, MHC molecules or PDGF . Stimulation of the NF-κB and the direct cell death resulting from ionizing radiation also stimulates invasion and activation of leukocytes leading to a productive immune response .
Cytokines can act to inhibit immune responses, e.g. IL-10 and TGF-β, while others like TNF-α, IFN--α and IL-1 are proinflammatory . TGF-α and IL-1 have been found to increase after sublethal total body irradiation, as have TGF-β and IL-6 . The release of these cytokines leads to recruitment and activation of leukocytes from peripheral blood and extravasation into tissue and tumors.
Insufficient migration of effector T lymphocytes may considerably account for the hitherto low clinical efficiency of clinical immunotherapy. Adhesion molecules such as ICAM-1, E- and particularly P-Selectin are located on the endothelial cell surface and mediate the immigration of effector T lymphocytes and other immune cells into human epithelial tumours . Vascular endothelial cells upregulate ICAM-1 and E-Selectin as a response to ionizing radiation and thereby facilitate leukocyte arrest and transmigration .
Chemokines are chemotactic cytokines that facilitate directional migration of cells expressing a cognate chemokine receptor. Two important chemokines regulated by ionizing radiation are CXCL-16 and SDF-1 . Mice deficient of CXCR6 (the CXCL-16 responding receptor) have been demonstrated to exhibit decreased CD8+ cell recruitment and radiotherapy responsiveness . It has also been demonstrated, that macrophage infiltration following RT was dependent on the SDF-1α expression. Thus ionizing radiation can regulate chemokines either via recruitment of tumor suppressive CD8 cells or tumor promoting cells such as macrophages.
Functional antigen-presentation is required for a productive anti-tumor T-cell response. Antigen-Presenting cells capture antigens and following processing present those on their cell surface vial major histocompatability complexes (MHC). T-cells recognize antigens bound to MHC and initiate anti-tumor response. Ionizing radiation also upregulates MHC class I on tumor cells and antigen-presenting cells  indicating that ionizing radiation can enhance tumor cell recognition by T-cells.
Moreover, ionizing radiation can activate endothelial cells thus facilitating the immigration of T-cells into the tumor. Overall, the available preclinical in vivo data support the hypothesis that radiation may provide at least some of the necessary maturation signals.
To date, no systematic clinical trial on the question if and how low dose radiotherapy can enhance immune activity in tumors. One question to address this is to determine the effective radiation dose to cause immune response. Furthermore, no data are yet available with respect to the specific radiosensitivity of the different cellular components of the immune system, or the microenvironment, and no data are available describing effects of radiation on circulating immune cells.
The here presented study describes a clinical phase I/II trial in pancreatic cancer patients with scheduled resection. The pancreatic cancer will be irradiated two days prior to planned surgery using precision external beam radiotherapy by photon intensity modulated radiotherapy (IMRT). Primary endpoints are the local radiation dose leading to tumor infiltrating T4 cells as a surrogate parameter for antitumor activity. Secondary objectives include clinical parameters such as local tumor control, patient survival, treatment related toxicity as well as quality of life of the patients. Furthermore, frequencies of tumor reactive T cells in blood and bone marrow will be correlated with blood cell whole genome transcriptional and plasma-protein analyses.