High Plus Low Dose Radiation Strategy in Combination with TIGIT and PD1 Blockade to Promote Systemic Antitumor Responses

Tumors deploy various immune-evasion mechanisms that create a suppressive environment and render effector T-cells exhausted and inactive. Therefore, a rational utilization of checkpoint inhibitors may alleviate exhaustion and may partially restore antitumor functions. However, in high-tumor-burden models, the checkpoint blockade fails to maintain optimal efficacy, and other interventions are necessary to overcome the inhibitory tumor stroma. One such strategy is the use of radiotherapy to reset the tumor microenvironment and maximize systemic antitumor outcomes. In this study, we propose the use of anti-PD1 and anti-TIGIT checkpoint inhibitors in conjunction with our novel RadScopal technique to battle highly metastatic lung adenocarcinoma tumors, bilaterally established in 129Sv/Ev mice, to mimic high-tumor-burden settings. The RadScopal approach is comprised of high-dose radiation directed at primary tumors with low-dose radiation delivered to secondary tumors to improve the outcomes of systemic immunotherapy. Indeed, the triple therapy with RadScopal + anti-TIGIT + anti-PD1 was able to prolong the survival of treated mice and halted the growth of both primary and secondary tumors. Lung metastasis counts were also significantly reduced. In addition, the low-dose radiation component reduced TIGIT receptor (PVR) expression by tumor-associated macrophages and dendritic cells in secondary tumors. Finally, low-dose radiation within triple therapy decreased the percentages of TIGIT+ exhausted T-cells and TIGIT+ regulatory T-cells. Together, our translational approach provides a new treatment alternative for cases refractory to other checkpoints and may bring immunotherapy into a new realm of systemic disease control.

U(VI) Adsorption onto Low Dose Radiation Acclimated Tradescantia Fluminensis

The plants that long-term grown in radiation area could be acclimated by low dose radiation (LDR). In this paper, LDR acclimated Tradescantia fluminensis (Commelinaceae) was first collected as a biomass adsorbent towards uranium adsorption. Comparative experiments verified the potential radiation effects of LDR acclimation, moreover, qe values of the wild and LDR acclimated Tradescantia fluminensis were ~16 mg/g and 20 mg/g, respectively. U(VI) adsorption amount gradually reached equilibrium after 180 min shaking, and the adsorption process described well by the pseudo-second-order model. However, ionic strength has no obvious effect on the qe values. SEM and TG-DSC suggested good structural stability of LDR acclimated Tradescantia fluminensis during the U(VI) adsorption process. FTIR and XPS verfied the surface coordination of U(VI) via -OH and -COOH groups on LDR acclimated Tradescantia fluminensis surface, and the increasing amounts of the two groups could account for the improved U(VI) adsorption capacity compared to the wild Tradescantia fluminensis. Our present work can indicate that LDR acclimation could be a novel way to obtain biomass adsorbents for U(VI) removal from aqueous solutions.

Evaluation of Global DNA Methylation and Gene Expression of Izumo1 and Izumo1r in Gonads after High- and Low-Dose Radiation in Neonatal Mice

The intergenerational effects from chronic low-dose exposure are matters of concern. It is thus important to elucidate the radiation-induced effects of germ cell maturation, fertilization and embryonic development. It is well known that DNA methylation levels in CpG sites in gametes are reprogrammed in stages during their maturity. Furthermore, the binding of Izumo on the surface of sperm and Juno on the surface of oocytes is essential for fertilization. Thus, there is a possibility that these genes are useful indicators to evaluate fertility in mice after irradiation exposure. Therefore, in this study, we analyzed global DNA methylation patterns in the testes and gene expression of Izumo1 and Izumo1r (Juno) in the gonads of mice after neonatal acute high-dose ionizing radiation (HDR) and chronic low-dose ionizing radiation (LDR). One-week-old male and female mice were irradiated with a total dose of 4 Gy, with acute HDR at 7 days at a dose rate of 30 Gy/h and LDR continuously at a dose rate of 6 mGy/h from 7 to 35 days. Their gonads were subsequently analyzed. The results of global DNA methylation patterns in the testes showed that methylation level increased with age in the control group, the LDR group maintained its DNA methylation level, and the HDR group showed decreased DNA methylation levels with age. In the control group, the gene expression level of Izumo1 in the testis did not show age-related changes, although there was high expression at 100 days of age. However, in the LDR group, the expression level recovered after the end of irradiation, while it remained low regardless of age in the HDR group. Conversely, gene expression of Izumo1r (Izumo1 receptor) in the ovary decreased with age in the control group. Although the gene expression of Izumo1r decreased with age in the LDR group, it remained low in the HDR group. Our results indicate that LDR can induce different DNA methylation patterns, and both high- and low-dose radiation before sexual maturity might affect gametogenesis and fertility.

A radioenhancing nanoparticle mediated immunoradiation improves survival and generates long-term antitumor immune memory in an anti-PD1-resistant murine lung cancer model

Background Combining radiotherapy with PD1 blockade has had impressive antitumor effects in preclinical models of metastatic lung cancer, although anti-PD1 resistance remains problematic. Here, we report results from a triple-combination therapy in which NBTXR3, a clinically approved nanoparticle radioenhancer, is combined with high-dose radiation (HDXRT) to a primary tumor plus low-dose radiation (LDXRT) to a secondary tumor along with checkpoint blockade in a mouse model of anti-PD1-resistant metastatic lung cancer. Methods Mice were inoculated with 344SQR cells in the right legs on day 0 (primary tumor) and the left legs on day 3 (secondary tumor). Immune checkpoint inhibitors (ICIs), including anti-PD1 (200 μg) and anti-CTLA4 (100 μg) were given intraperitoneally. Primary tumors were injected with NBTXR3 on day 6 and irradiated with 12-Gy (HDXRT) on days 7, 8, and 9; secondary tumors were irradiated with 1-Gy (LDXRT) on days 12 and 13. The survivor mice at day 178 were rechallenged with 344SQR cells and tumor growth monitored thereafter. Results NBTXR3 + HDXRT + LDXRT + ICIs had significant antitumor effects against both primary and secondary tumors, improving the survival rate from 0 to 50%. Immune profiling of the secondary tumors revealed that NBTXR3 + HDXRT + LDXRT increased CD8 T-cell infiltration and decreased the number of regulatory T (Treg) cells. Finally, none of the re-challenged mice developed tumors, and they had higher percentages of CD4 memory T cells and CD4 and CD8 T cells in both blood and spleen relative to untreated mice. Conclusions NBTXR3 nanoparticle in combination with radioimmunotherapy significantly improves anti-PD1 resistant lung tumor control via promoting antitumor immune response. Graphical Abstract

Comparative analysis of population mortality in the cities of Severodvinsk and Arkhangelsk

Increasing use of ionizing radiation sources in different spheres of human life dictates the need for investigating the effects of low-dose radiation on mortality and morbidity. The aim of this study was to compare mortality from the most common non-communicable diseases in the cities of Severodvinsk and Arkhangelsk. We analyzed the rates of age- and sex-specific mortality from circulatory system diseases (CSD), malignancies, digestive system disorders, respiratory system diseases, and external causes. CSD-related mortality among men and women past working age was higher in Severodvinsk than in Arkhangelsk (median (Q1; Q3): 3,349 (3,271; 3,458) vs 2,651 (2,618; 2,756), p < 0.012; 1,947 (1,890; 2,022) vs 1,753 (1,727; 1,809), p < 0.012; 292 (281; 342) vs 265 (253; 274), p < 0.025, respectively). For other causes of death, mortality rates in Severodvinsk did not exceed those in Arkhangelsk. Increased mortality from CSD in Severodvinsk cannot be linked to socioeconomic conditions or chemical air pollution because the standard of living is higher in Severodvinsk than in Arkhangelsk, whereas the level of chemical pollution is lower. At the same time, the presence of the nuclear shipyard and radioactive waste repository in Severodvinsk could cause chronic exposure to low-dose radiation. It is important to expand preventive measures aimed at early detection of vascular damage in nuclear workers and general groups of population residing in the vicinity of hazardous radiation sites.