Abscopal mutagenic effect of low-energy-ions in Arabidopsis Thaliana seeds

Abstract

Purpose: To demonstrate the abscopal mutagenic effect of low-energy-ion irradiation in dormant plant seeds, and its dependence on the targeted portion of seeds.

Materials and methods: Arabidopsis thaliana-lines transgenic for b-glucuronidase (GUS) recombination substrates and A. thaliana RADiation54 (AtRAD54) promoter::GUS were adopted. The seeds were irradiated from four specialised orientations with 30 KeV ⁴⁰Ar⁺ ions. The homologous recombination frequency (HRF) and the expression levels of the AtRAD54 genein non-irradiated aerial plants were measured. Moreover, several post-embryonic developments, such as growth of primary roots, differentiation of root hairs, and germination of seeds and growth of true leaves, were also analysed.

Results: It was shown that low-energy-ion irradiation of seeds led to significant increases in HRF in the non-irradiated aerial parts of irradiated plants and the aerial parts of naïve plants from irradiated progenitors. The low-energy-ion irradiation was also shown to induce an elevated expression of AtRAD54 gene in aerial plants, and to inhibit the post-embryonic developments of seeds. Moreover, the changes in HRF, expression level of the AtRAD54 gene and post-embryonic developments depended largely on the orientation of seeds with regard to low-energy-ion irradiation; and the root apical meristem (RAM)-orientated irradiation exhibited the largest effects on all biological endpoints assayed here.

Conclusions: Low-energy-ion irradiation can induce an abscopal mutagenic effect in dormant plant seeds, the extent of which depends greatly on the targeted portion of seeds.     

Efficacy of late concurrent hypofractionated radiotherapy in advanced melanoma patients failing anti-PD-1 monotherapy

Advanced melanoma patients who failed anti-PD-1 therapy have limited options. We analyzed a cohort of 133 advanced melanoma patients receiving anti-PD-1 monotherapy in a referral center between April 2015 and December 2017, and included the 26 patients with confirmed progressive (PD) or stable disease who received additional radiotherapy with an unmodified anti-PD-1 mAb regimen. Tumor evaluations were done on radiated and nonradiated (RECIST 1.1) lesions, with abscopal effect defined as a partial (PR) or complete response (CR) outside radiated fields. Primary endpoint was the CR + PR rate in radiated + nonradiated lesions. Secondary endpoints were progression-free survival (PFS), melanoma-specific survival (MSS) and safety. First late radiotherapy, consisting of hypofractionated radiotherapy (3–5 sessions, 20–26 Gy), standard palliative radiotherapy or brain radiosurgery was begun after a median of 6.3 months of anti-PD-1 in 23, 2 and 1 patient(s), respectively. Best response was 8 (31%) CR, 2 (8%) profound PR allowing surgical resection of remaining metastases and 16 (62%) PD. Abscopal effect was seen in 35% of patients. Median PFS and MSS since anti-PD-1 initiation was 15.2 [95% CI: 8.0 not achieved (na)] and 35.3 [95% CI: 18.5 na] months, respectively. PFS curves seemed to achieve a plateau. We discontinued anti-PD-1 therapy in 9/10 of patients with no residual evaluable disease and observed one relapse after a median of 10 months off anti-PD1-therapy. No unusual adverse event was recorded. Limitations of the study include its retrospective nature and limited size. Hypofractionated radiotherapy may enhance anti-PD1 monotherapy efficacy in patients who previously failed anti-PD-1 therapy. Controlled studies are needed.     

Sonodynamic therapy‐assisted immunotherapy: A novel modality for cancer treatment

Sonodynamic therapy (SDT), which is based on photodynamic therapy (PDT), is a new cancer treatment modality. Unlike PDT, which has poor tissue penetration, ultrasound can penetrate deeply into tissues and largely target tumor tissue to mediate the cytotoxicity of sonosensitizers. We hypothesize that, similar to PDT, SDT may perform effectively as a cancer vaccine. Thus, we developed a therapeutic strategy to explore whether SDT can eliminate primary tumors, inhibit metastases, and prevent tumor relapse. In the present study, we found that HiPorfin (HPD)‐induced SDT killed tumor cells, promoted calreticulin expression on the cell surface and elicited immune responses. Meanwhile, we observed that SDT induced functional antitumor vaccination and abscopal effects in H22 tumor‐bearing mice. Furthermore, this strategy conferred an immunological memory, which could protect against tumor recurrence after the elimination of the initial tumor. These results showed important effects of SDT on immune responses.     

Recent Advances in Pathology: the 2019 Annual Review Issue of The Journal of Pathology

In this Annual Review Issue of The Journal of Pathology, we present 15 invited reviews on topical aspects of pathology, ranging from the impacts of the microbiome in human disease through mechanisms of cell death and autophagy to recent advances in immunity and the uses of genomics for understanding, classifying and treating human cancers. Each of the reviews is authored by experts in their fields and our intention is to provide comprehensive updates in specific areas of pathology in which there has been considerable recent progress. Copyright © 2019 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.     

Abscopal effect of radiation therapy: Interplay between radiation dose and p53 status

Abstract

Purpose: This study investigates whether the abscopal effect induced by radiation-therapy (RT) is able to sterilize non-irradiated tumour cells through bystander signals.

Material and methods: Wild-type (wt)-p53 or p53-null HCT116 human colon cancer cells were xenografted into both flanks of athymic female nude mice. When tumours reached a volume of 0.2 cm³, irradiation was performed, under strict dose monitoring, with a dedicated mobile accelerator designed for intra-Operative-RT (IORT). A dose of 10 or 20 Gy (IR groups), delivered by a 10 MeV electron beam, was delivered to a tumour established in one side flank, leaving the other non-irradiated (NIR groups). A subset of mice were sacrificed early on to carry out short-term molecular analyses.

Results: All directly-irradiated tumours, showed a dose-dependent delayed and reduced regrowth, independent of the p53 status. Importantly, a significant effect on tumour-growth inhibition was also demonstrated in NIR wt-p53 tumours in the 20 Gy-irradiation group, with a moderate effect also evident after 10 Gy-irradiation. In contrast, no significant difference was observed in the NIR p53-null tumours, independent of the dose delivered. Molecular analyses indicate that p53-dependent signals might be responsible for the abscopal effect in our model system, via a pro-apoptotic pathway.

Conclusions: We suggest that the interplay between delivered dose and p53 status might help to sterilize out-of-field tumour cells.     

Spontaneous regression of metastatic melanoma – Clinical evidence of the abscopal effect

Introduction

Metastatic melanoma is poorly understood. Regression of primary lesions has been associated with poor prognosis, but spontaneous regression of all metastatic disease is clearly beneficial. A patient's own immune responses occasionally appear to stimulate spontaneous regression of metastatic disease in melanoma.

Patients and methods

We present six interesting cases of complete or nearly complete spontaneous regression of metastatic melanoma, suggest possible causes and review the literature.

Results and conclusions

These cases show clear radiological, pathological or clinical evidence of spontaneous regression of metastatic melanoma. This remains a poorly understood phenomena warranting further investigation and may prove useful in the development of immune mediated solutions.     

Local oncolytic adenovirotherapy produces an abscopal effect via tumor-derived extracellular vesicles

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Simultaneous targeting of TGF-β/PD-L1 synergizes with radiotherapy by reprogramming the tumor microenvironment to overcome immune evasion

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Old and new facts about hyperthermia-induced modulations of the immune system

Hyperthermia (HT) is a potent sensitiser for radiotherapy (RT) and chemotherapy (CT) and has been proven to modulate directly or indirectly cells of the innate and adaptive immune system. We will focus in this article on how anti-tumour immunity can be induced by HT. In contrast to some in vitro assays, in vivo examinations showed that natural killer cells and phagocytes like granulocytes are directly activated against the tumour by HT. Since heat also activates dendritic cells (DCs), HT should be combined with further death stimuli (RT, CT or immune therapy) to allocate tumour antigen, derived from, for example, necrotic tumour cells, for uptake by DCs. We will outline that induction of immunogenic tumour cells and direct tumour cell killing by HT in combination with other therapies contributes to immune activation against the tumour. Studies will be presented showing that non-beneficial effects of HT on immune cells are mostly timely restricted. A special focus is set on immune activation mediated by extracellular present heat shock proteins (HSPs) carrying tumour antigens and further danger signals released by dying tumour cells. Local HT treatment in addition to further stress stimuli exerts abscopal effects and might be considered as in situ tumour vaccination. An increased natural killer (NK) cell activity, lymphocyte infiltration and HSP-mediated induction of immunogenic tumour cells have been observed in patients. Treatments with the addition of HT therefore can be considered as a personalised cancer treatment approach by specifically activating the immune system against the individual unique tumour.