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Radiotherapy is under investigation for its ability to enhance responses to immunotherapy. However, the mechanisms by which radiation induces anti-tumour T cells remain unclear. We show that the DNA exonuclease Trex1 is induced by radiation doses above 12–18 Gy in different cancer cells, and attenuates their immunogenicity by degrading DNA that accumulates in the cytosol upon radiation. Cytosolic DNA stimulates secretion of interferon-β by cancer cells following activation of the DNA sensor cGAS and its downstream effector STING. Repeated irradiation at doses that do not induce Trex1 amplifies interferon-β production, resulting in recruitment and activation of Batf3-dependent dendritic cells. This effect is essential for priming of CD8+ T cells that mediate systemic tumour rejection (abscopal effect) in the context of immune checkpoint blockade. Thus, Trex1 is an upstream regulator of radiation-driven anti-tumour immunity. Trex1 induction may guide the selection of radiation dose and fractionation in patients treated with immunotherapy.

Physicians, hospitals, and other health care facilities will assume the responsibility for aiding individuals injured by a terrorist act involving radioactive material. Scenarios have been developed for such acts that include a range of exposures resulting in few to many casualties. This consensus document was developed by the Strategic National Stockpile Radiation Working Group to provide a framework for physicians in internal medicine and the medical subspecialties to evaluate and manage large-scale radiation injuries. Individual radiation dose is assessed by determining the time to onset and severity of nausea and vomiting, decline in absolute lymphocyte count over several hours or days after exposure, and appearance of chromosome aberrations (including dicentrics and ring forms) in peripheral blood lymphocytes. Documentation of clinical signs and symptoms (affecting the hematopoietic, gastrointestinal, cerebrovascular, and cutaneous systems) over time is essential for triage of victims, selection of therapy, and assignment of prognosis. Recommendations based on radiation dose and physiologic response are made for treatment of the hematopoietic syndrome. Therapy includes treatment with hematopoietic cytokines; blood transfusion; and, in selected cases, stem-cell transplantation. Additional medical management based on the evolution of clinical signs and symptoms includes the use of antimicrobial agents (quinolones, antiviral therapy, and antifungal agents), antiemetic agents, and analgesic agents. Because of the strong psychological impact of a possible radiation exposure, psychosocial support will be required for those exposed, regardless of the dose, as well as for family and friends. Treatment of pregnant women must account for risk to the fetus. For terrorist or accidental events involving exposure to radioiodines, prophylaxis against malignant disease of the thyroid is also recommended, particularly for children and adolescents.

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ABSTRACT

Purpose: Many patients with clinically localized prostate cancer develop biochemical failure despite excellent local therapy perhaps due to occult metastatic disease. One potential solution is the utilization of a well-tolerated systemic therapy (e.g., vaccine) in concert with local therapy. Experimental Design:We present a randomized phase II clinical trial designed to determine if a poxviral vaccine encoding prostate-specific antigen (PSA) can induce a PSA-specific T-cell response when combined with radiotherapy in patients with clinically localized prostate cancer. Thirty patients were randomized in a 2:1 ratio into vaccine plus radiotherapy or radiotherapyonly arms. Those patients in the combination arm received a ''priming'' vaccine with recombinant vaccinia (r V) PSA plus r V containing theT-cell costimulatory molecule B7.1 (r V-B7.1) followed by monthly booster vaccines with recombinant fowlpox PSA. The vaccines were given with local granulocyte-macrophage colony-stimulating factor andlow-dose systemicinterleukin-2. Standard external beam radiation therapy was given between the fourth and the sixth vaccinations. Results: Seventeen of 19 patients in the combination arm completed all eight vaccinations and 13 of these 17 patients had increases in PSA-specificTcells of at least 3-fold versus no detectable increases in the radiotherapy-only arm (P <0.0005).There was also evidence ofde novo generation of T cells to well-described prostate-associated antigens not found in the vaccine, providing indirect evidence of immune-mediated tumor killing. The vaccine was well tolerated. Conclusion:This vaccine regimen can be safely given in patients undergoing radiation therapy for localized prostate cancer, with the majority of patients generating a PSA-specific cellular immune response to vaccine.

We estimated the risk of second cancers among 1507 patients with Hodgkin's disease treated at Stanford University Medical Center since 1968. Eight-three second cancers occurred more than one year after diagnosis, as compared with 15.9 expected on the basis of rates in the general population (relative risk, 5.2; 95 percent confidence interval, 4.2 to 6.5). The mean (+/- SE) 15-year actuarial risk of all second cancers was 17.6 +/- 3.1 percent, of which 13.2 +/- 3.1 percent was due to solid tumors. The risk of leukemia appeared to reach a plateau level of 3.3 +/- 0.6 percent at 10 years, whereas non-Hodgkin's lymphoma continued to increase, to 1.6 +/- 0.7 percent by the end of the follow-up period. The risk of solid tumors did not vary significantly according to treatment category, with the array of neoplasms resembling that previously observed in populations exposed to radiation and in immunosuppressed groups. The risk of leukemia, although elevated after radiation therapy alone (relative risk, 11; 95 percent confidence interval, 1.2 to 38), was much higher after either adjuvant chemotherapy (relative risk, 117; 95 percent confidence interval, 69 to 185) or chemotherapy alone (relative risk, 130; 95 percent confidence interval, 26 to 380). These data suggest that the risk of solid tumors after therapy for Hodgkin's disease continues to increase with time.

Apoptotic pathways controlled by the Rel/NF-kB family of transcription factors may regulate the response of cells to DNA damage. Here, we have examined the NFkB status of several prostate tumor cell lines. In the androgen-independent prostate tumor cells PC-3 and DU-145, the DNA-binding activity of NF-kB was constitutively activated and IkB-a levels were decreased. In contrast, the androgen-sensitive prostate tumor cell line LNCaP had low levels of NF-kB which were upregulated following exposure to cytokines or DNA damage. The activity of the IkB-a kinase, IKKa, which mediates NF-kB activation, was also measured. In PC-3 cells, IKKa activity was constitutively active, whereas LNCaP cells had minimal IKKa activity that was activated by cytokines. The anti-in¯ammatory agent ibuprofen inhibited the constitutive activation of NF-kB and IKKa in PC-3 and DU-145 cells, and blocked stimulated activation of NF-kB in LNCaP cells. However, ibuprofen did not directly inhibit IkB-a kinase. The results demonstrate that NF-kB is constitutively activated in the hormone-insensitive prostate tumor cell lines PC-3 and DU-145, but not in the hormone responsive LNCaP cell line. The constitutive activation of NF-kB in prostate tumor cells may increase expression of anti-apoptotic proteins, thereby decreasing the e ectiveness of anti-tumor therapy and contributing to the development of the malignant phenotype.