Androgen receptor-mediated CD8+ T cell stemness programs drive sex differences in antitumor immunity.

The incidence and mortality rates of many non-reproductive human cancers are generally higher in males than in females. However, the immunological mechanism underlying sexual differences in cancers remains elusive. Here, we demonstrated that sex-related differences in tumor burden depended on adaptive immunity. Male CD8+ T cells exhibited impaired effector and stem cell-like properties compared with female CD8+ T cells. Mechanistically, androgen receptor inhibited the activity and stemness of male tumor-infiltrating CD8+ T cells by regulating epigenetic and transcriptional differentiation programs. Castration combined with anti-PD-L1 treatment synergistically restricted tumor growth in male mice. In humans, fewer male CD8+ T cells maintained a stem cell-like memory state compared with female counterparts. Moreover, AR expression correlated with tumor-infiltrating CD8+ T cell exhaustion in cancer patients. Our findings reveal sex-biased CD8+ T cell stemness programs in cancer progression and in the responses to cancer immunotherapy, providing insights into the development of sex-based immunotherapeutic strategies for cancer treatment.

LncRNA SNHG11 induces ferroptosis in liver injury cells through miR-324-3p/GPX4 axis-mediated sepsis.

Sepsis is a kind of systemic inflammatory response syndrome caused by infection, which has high morbidity and mortality. Studies have shown that reducing sepsis-related liver injury and restoring liver function can reduce the morbidity and mortality of it. Current clinical treatment methods for sepsis have many disadvantages. Our study aimed to investigate the mechanism of sepsis-induced liver injury and to find a proper therapeutic target for sepsis. In this paper, we have found that when miR-324-3p was overexpressed, the inflammatory infiltration and and ferroptosis in liver injury cells aggravated. Further studies showed that overexpression of miR-324-3p could bind to the 3'-UTR of SNHG11 directly so as to decrease the expression level of SNHG11. Our study indicated that LncRNA SNGH11 can mediate the ferroptosis of liver injury cells induced by sepsis through the miR-324-3p/GPX4 axis. Suggesting that it is a new drug target for clinical treatment of sepsis and sepsis-associated liver injury, then we can improve the survival rate for sepsis patients.

Impacts of emissions and meteorological conditions in three different phases of aerosol pollution during 2013-2022 in Anhui, China.

The PM2.5 concentrations in Anhui, which links the Yangtze River Delta region, China's fastest growing economy area, with the Beijing-Tianjin-Hebei (BTH) region, China's most polluted region, are influenced not only by emissions, but also by variation of meteorological conditions. A comprehensive understanding of the relative impacts of meteorology and emissions on heavy pollution in Anhui at three phases (i.e., phase1: from 2013 to 2017; phase2: from 2018 to 2020; phase 3: from 2021 to 2022) from 2013 to 2022, which can provide suggestions for pollution prevention and control in the future. The decrease in pollutant concentrations from 2013 to 2022 is mainly attributed to the continued reduction in emissions, while the year-to-year fluctuations in pollutant concentrations are largely influenced by meteorological conditions. Although emissions are decreasing, the proportions of residential biofuel combustion and cement are increasing. In addition to the effects of prevailing northeasterly and northwesterly winds (i.e., Type1 and Type2), there is also concern about the influences of static weather and neighboring regional transport (i.e., Type5 and Type6), especially in 2016. The contribution of emissions is greater in phase 2 and phase 3, with a 17 % increase compared to phase 1. Overall, approximately 57 % of explosive growth in PM2.5 concentration during the cumulative stage (CS) can be regarded as the feedback effect of the deteriorating meteorological conditions. Therefore, statistical analyses show that limiting PM2.5 concentrations below about 73 µg m-3 would weaken the feedback effects, which in turn would avoid most of the explosive growth processes in the CS of the 60 heavy pollution processes, which can provide a reference for the government to set a target for sustained emission reduction.

Cell-intrinsic PD-L1 ablation sustains effector CD8+ T cell responses and promotes antitumor T cell therapy.

Adoptive cell therapies are emerging forms of immunotherapy that reprogram T cells for enhanced antitumor responses. Although surface programmed cell death-ligand 1 (PD-L1)/programmed cell death protein 1 (PD-1) engagement inhibits antitumor immunity, the role of cell-intrinsic PD-L1 in adoptive T cell therapy remains unknown. Here, we found that intracellular PD-L1 was enriched in tumor-infiltrating CD8+ T cells of cancer patients. PD-L1 ablation promoted antitumor immune responses and the maintenance of an effector-like state of therapeutic CD8+ T cells, while blockade of surface PD-L1 was unable to impact on their expansion and function. Moreover, cell-intrinsic PD-L1 impeded CD8+ T cell activity, which partially relied on mTORC1 signaling. Furthermore, endogenous tumor-reactive CD8+ T cells were motivated by BATF3-driven dendritic cells after adoptive transfer of PD-L1-deficient therapeutic CD8+ T cells. This role of cell-intrinsic PD-L1 in therapeutic CD8+ T cell dysfunction highlights that disrupting cell-intrinsic PD-L1 in CD8+ T cells represents a viable approach to improving T cell-based cancer immunotherapy.

Noncanonical MAVS signaling restrains dendritic cell-driven antitumor immunity by inhibiting IL-12.

Mitochondrial antiviral signaling protein (MAVS)-mediated cytosolic RNA sensing plays a central role in tumor immunogenicity. However, the effects of host MAVS signaling on antitumor immunity remain unclear. Here, we demonstrate that the host MAVS pathway supports tumor growth and impairs antitumor immunity, whereas MAVS deficiency in dendritic cells (DCs) promotes tumor-reactive CD8+ T cell responses. Specifically, CD8+ T cell priming capacity was enhanced by MAVS ablation in a type I interferon-independent, but IL-12-dependent, manner. Mechanistically, loss of the RIG-I/MAVS cascade activated the noncanonical NF-κB pathway and in turn induced IL-12 production by DCs. MAVS-restrained IL-12 promoted cross-talk between CD8+ T cells and DCs, which was licensed by IFN-γ. Moreover, ablation of host MAVS sensitized tumors to immunotherapy and attenuated radiation resistance, thereby facilitating the maintenance of effector CD8+ T cells. These findings demonstrate that the host MAVS pathway acts as an immune regulator of DC-driven antitumor immunity and support the development of immunotherapies that antagonize MAVS signaling in DCs.

STING signaling promotes NK cell antitumor immunity and maintains a reservoir of TCF-1+ NK cells.

Natural killer (NK) cells are cytotoxic innate lymphocytes that eradicate tumor cells. Inducing durable antitumor immune responses by NK cells represents a major priority of cancer immunotherapy. While cytosolic DNA sensing plays an essential role in initiating antitumor immunity, the role of NK cell-intrinsic STING signaling remains unclear. Here, we find that NK cell-intrinsic STING promotes antitumor responses and maintains a reservoir of TCF-1+ NK cells. In contrast, tumor cell-intrinsic cGAS and mtDNA are required for NK cell antitumor activity, indicating that tumor mtDNA recognition by cGAS partially triggers NK cell-intrinsic STING activation. Moreover, addition of cGAMP enables STING activation and type I interferon production in NK cells, thereby supporting the activation of NK cells in vitro. In humans, STING agonism promotes the expansion of TCF-1+ NK cells. This study provides insight into understanding how STING signaling drives NK cell antitumor immunity and the development of NK cell-based cancer immunotherapy.

[Meteorological Impact Assessment of PM2.5 and O3 Complex Pollution in Key Regions of China Based on Meteorological Conditions Index].

Meteorological conditions play a key role in the occurrence and evolution of atmospheric complex pollution. Considering the different pollution formation mechanisms of PM2.5 and O3, statistical calculation and in-depth learning methods were used to construct the PM2.5 and O3 meteorological condition indexes based on long-term pollution meteorological observation data. A research method was developed to study the meteorological characteristics and impact contribution of atmospheric complex pollution by using the meteorological condition index, and quantitative analysis of the distribution and variation of pollution excluding the influence of regional meteorological differences was also conducted. The results showed that in the summer of 2021, the pollution meteorological conditions in the key regions in central and eastern China were generally worse in the north and better in the south(index:"2+26" cities>the border area of Jiangsu, Anhui, Shandong, and Henan>the Yangtze River Delta) and the worst in June and the best in July. The "double high" pollution began to appear when the PM2.5 meteorological condition index>30 and O3 meteorological condition index>100; meanwhile, the unfavorable meteorological conditions for O3 also promoted the increase in PM2.5 concentration, resulting in the frequency of "double high" increases with the increase in O3 meteorological condition index. Compared with that during the same period last year, ρ(PM2.5) of each region decreased by 3.9 µg·m-3, 3.3 µg·m-3, and 1.4 µg·m-3 due to the contribution of the improvement in the pollution meteorological conditions, which is nearly 58.5% on average of the total decrease in PM2.5 concentration. However, the change in O3 pollution meteorological conditions was better in the north and worse in the south, and the overall deterioration in the Yangtze River Delta Region led to approximately 2.8 µg·m-3 growth for the O3 concentration. The PM2.5 and O3 concentrations after excluding the impact of meteorological differences showed different distribution characteristics from the air quality monitoring, in which the high concentrations of PM2.5 were distributed along the Bohai Sea, the inter-provincial border, and the south of the region, whereas the high concentrations of O3 were concentrated along the Taihang Mountains, around Mount Tai, and in parts of the Yangtze River Delta. The daily concentration variations in a single city during a specific pollution control period could be used as a basis for evaluating the effectiveness of local supervision and control, which will provide a reference for the dynamic supervision and daily scheduling of local control management.

Impact of air pollution control measures and weather conditions on asthma during the 2008 Summer Olympic Games in Beijing.

The alternative transportation strategy implemented during the 2008 Summer Olympic Games in Beijing provided an opportunity to study the impact of the control measures and weather conditions on air quality and asthma morbidity. An ecological study compared the 41 days of the Olympic Games (8 August-17 September 2008) to a baseline period (1-30 June). Also, in order to emphasize the impact of weather conditions on air quality, a pollution linking meteorological index (Plam) was introduced to represent the air pollution meteorological condition. Our study showed that the average number of outpatient visits for asthma was 12.5 per day at baseline and 7.3 per day during the Olympics-a 41.6% overall decrease. Compared with the baseline, the Games were associated with a significant reduction in asthma visits (RR 0.58, 95%CI: 0.52-0.65). At 16.5 visits per day, asthma visits were also significantly higher, during the pre-Olympic period (RR 1.32, 95% CI: 1.15-1.52). The study also showed that the RR of asthma events on a given day, as well as the average daily peak ozone concentration during the preceding 48-72 h, increased at cumulative ozone concentrations of 70 to 100 ppb and 100 ppb or more compared with ozone concentrations of less than 70 ppb (P < 0.05). We concluded that along with "good" weather conditions, efforts to reduce traffic congestion in Beijing during the Olympic Games were associated with a prolonged reduction in air pollution and significantly lower rates of adult asthma events. These data provide support for efforts to reduce air pollution and improve health via reductions in motor vehicle traffic.

The influence of stagnant and transport types weather on heavy pollution in the Yangtze-Huaihe valley, China.

The ambient atmospheric PM2.5 concentrations in Anhui Province, China, which links the Yangtze River Delta region, China's fastest growing economy area, with the Beijing-Tianjin-Hebei (BTH) region, China's most polluted region, are influenced not only by local emissions, but also by changes in regional circulation. During the period 2013-2017, when China adopted a series of pollution abatement measures, there were still occasional pollution episodes with significant increases in PM2.5 concentrations. PM2.5 rise instead during the period 2013-2017 in Anhui (the Center of the Yangtze-Huaihe, YH), when pollution emissions continued to decrease? What is the controlling mechanism behind these? By analyzing elements such as ground-based PM2.5 concentration and the planetary boundary layer (PBL) structure affecting it as well as larger scale circulation, combined with the analysis of a parameterized index, one can find that aerosol pollution in the YH region can usually be classified into three types. (1) There is a short-term transport stage (TS) in the initial stage of pollution, then as the pollutant concentrations increase, the PBL height decreases, the temperature inversion is gradually formed or strengthened, the wind speed decreases and the relative humidity of the lower layer increases, forming a two-way feedback mechanism in the cumulative stage (CS). (2) Pollutant concentrations will not drop rapidly in the later stage of CS, while a short-term TS will occur again. (3) The explosive rise (ER) events are mainly affected by transportation in the YH. The first of these types tends to be accompanied by the emergence and maintenance of heavy pollution periods (HPEs), and some phases is accompanied by explosive rises (ERs) in PM2.5 that at least double in a short period of time. To sum up, deterioration of meteorological conditions explaining approximately 68% to the increase in PM2.5 in the ER.

ZBP1-MLKL necroptotic signaling potentiates radiation-induced antitumor immunity via intratumoral STING pathway activation.

Necroptosis, a form of regulated necrosis, participates in tumor development and dying cell immunogenicity. However, it remains unclear how tumor cell­intrinsic necroptotic signaling contributes to radiation-induced antitumor immunity. Here, we found that the ZBP1-MLKL necroptotic cascade in irradiated tumor cells was essential for antitumor immunity. ZBP1-dependent activation of MLKL potentiated type I interferon responses following tumor cell irradiation. Mechanistically, the ZBP1-MLKL necroptotic cascade induced cytoplasmic DNA accumulation in irradiated tumor cells and, in turn, autonomously activated cGAS-STING signaling, thus creating a positive feedback loop between those two pathways to drive persistent inflammation. Accordingly, ablation of caspase-8 enhanced STING pathway activation and the antitumor effects of radiation by activating MLKL. These findings reveal that ZBP1-MLKL necroptosis signaling maximized radiation-induced antitumor immunity through mutual interaction with the tumor cell­intrinsic STING pathway. This study provides insight into how radiotherapy bridges tumor cell damage to antitumor immune responses and an alternative strategy to improve radiotherapy.

The two-way feedback effect between aerosol pollution and planetary boundary layer structure on the explosive rise of PM2.5 after the "Ten Statements of Atmosphere" in Beijing.

Are there still persistent heavy aerosol pollution episodes (HPEs) in Beijing one year after the implementation of the "Action Plan for the Prevention and Control of Air Pollution ("Ten Statements of Atmosphere" in China: 2013-2017)"? Will the cumulative aerosol pollution still induce significant two-way feedback between PM2.5 and the planetary boundary layer structure? Answers to these matters are particular concerns of the government and the public. The analysis of the vertical structure of the aerosol and meteorological factors in planetary boundary layer shows that the two-way feedback between unfavorable meteorological conditions and PM2.5 pollution cumulating is still the primary mechanism for the maintenance of HPEs, accounting especially ~66% to 88% for explosive rise in PM2.5, in autumn and winter in Beijing area a year after the "Ten Statements of Atmosphere". This effect also shows that the concentration of PM2.5 in Beijing had not fallen low enough to decouple the influence of unfavorable meteorological factors. The increased level of PM2.5 mass during the explosive rise stage was similar to those of the precursor gases of NO2, SO2 and CO, as well as to the declining ratio of the boundary layer height (BLH), which also suggest that the interaction between PM2.5 cumulating and the boundary layer structure is playing a leading role for the maintenance of HPEs and the PM2.5 explosive rise in Beijing. The depolarization ratio signal of the Lidar also shows that the transit of mineral aerosols from the northwest over Beijing often appears in the upper layer of the planetary boundary layer or higher atmosphere during the late or subside stage of HPEs.

cGAS-STING-mediated DNA sensing maintains CD8+ T cell stemness and promotes antitumor T cell therapy.

Although cGAS-STING-mediated DNA sensing in tumor cells or phagocytes is central for launching antitumor immunity, the role of intrinsic cGAS-STING activation in T cells remains unknown. Here, we observed that peripheral blood CD8+ T cells from patients with cancer showed remarkably compromised expression of the cGAS-STING cascade. We demonstrated that the cGAS-STING cascade in adoptively transferred CD8+ T cells was essential for antitumor immune responses in the context of T cell therapy in mice. Mechanistically, cell-autonomous cGAS and STING promoted the maintenance of stem cell-like CD8+ T cells, in part, by regulating the transcription factor TCF1 expression. Moreover, autocrine cGAS-STING-mediated type I interferon signaling augmented stem cell-like CD8+ T cell differentiation program mainly by restraining Akt activity. In addition, genomic DNA was selectively enriched in the cytosol of mouse CD8+ T cells upon in vitro and in vivo stimulation. STING agonism enhanced the formation of stem-like central memory CD8+ T cells from patients with cancer and potentiated antitumor responses of CAR-T cell therapy in a xenograft model. These findings advance our understanding of inherent cGAS-STING activation in T cells and provide insight into the development of improved T cell therapy by harnessing the cGAS-STING pathway for cancer immunotherapy.

Influence of meteorological conditions on explosive increase in O3 concentration in troposphere.

Ozone (O3) pollution in the troposphere, especially at the surface layer, has become a focus of attention in recent years. High O3 concentration events tend to occur frequently in north China, Yangtze, the Pearl River Delta, and the Sichuan Basin, among others. Studies on the meteorological contribution to O3 in the troposphere have become a new direction for the scientific community. This research intends to explore how meteorological conditions contribute to O3 pollution in all seasons on the basis of further studies of the PLAM index. Our findings are as follows. (1) In pollution-sensitive areas, following a height uplift in the pollution mixing layer (H_PML), NO2 concentration decreases initially, followed by an explosive increase (EI) in O3 concentration after sunrise. (2) This process varies significantly by season and area. (3) According to an analysis of the meteorological conditions causing rises in O3 concentration within a few hours after sunrise, the initial decrease-subsequent increase in NO2 versus O3 concentration satisfies the law of exponent power rule, according to which seasonal and regional differences in coastal and inland areas depend on coefficients α and ß. The explosive increase in O3 concentration, decrease in NO2 concentration, and characteristics of their diurnal cycles are also discussed. (4) Under the meteorological condition of static stability, below the static and stable cover, the H_PML of the polluted mixed layer consistently indicates the reciprocating cycle of day uplift and night pressure. The effect of air pump suction on the pollutant is an important mechanism of large-scale pollution in the study area under the condition of static and stable cover. (5) The influencing mechanism of meteorological conditions in the diurnal H_PML cycle aids in improving the understanding of O3 concentration increases in the troposphere.

Global view on China's foggy-haze associated with air-pollutant conveyor belts.

Upper air and surface data from 1960 to 2016, NCEP reanalysis from 1990 to 2016, air composition data from 2015 to 2016, and data from the drift automatic weather station in the Arctic from August 2012 to February 2013 are used to analyze the heavy foggy haze in China from a global perspective. Our findings show that sensitive foggy haze in winter is located in the eastern region of China because of the comprehensive effect of multi-factor meteorological conditions and the response to climate change under global warming as follows. (1) For the past half-century, two winter monsoon airflows blow from the East Asian continent and adjacent sea to North China. The airflow in the intermediate zone (North China) between the two winter monsoon airflows generates a retained circulation owing to the Earth's rotation because wind velocities over land and sea are different and their wind intensities are weakened. The circulation retention index has been on the rise in recent years, causing a "static stability" that retains or stabilizes air masses over this area. (2) Under global warming, polar ice has shrunk to a historical lowest over the years. The melting polar ice results in explosive heating and humidification in the lower troposphere leading to increased aerosol concentrations, which is conducive to maintaining or strengthening the Arctic haze. (3) The two winter monsoon pathways run over the Eurasian continent and the surface of the adjacent Sea of Okhotsk, thus affecting North China. These results are consistent with the airflow of the pollutant conveyor belt channeling from the Arctic haze zone. As a result, the pollutant conveyor belt from the Arctic haze zone as well as the pollutant conveyor belts from West Asia and North Africa contribute substantially to the high frequency of winter foggy haze over eastern China.

Interdecadal changes of summer aerosol pollution in the Yangtze River Basin of China, the relative influence of meteorological conditions and the relation to climate change.

Winter is a season of much concern for aerosol pollution in China, but less concern for pollution in the summertime. There are even less concern and larger uncertainty about interdecadal changes in summer aerosol pollution, relative influence of meteorological conditions, and their links to climate change. Here we try to reveal the relation among interdecadal changes in summer's most important circulation system affecting China (East Asian Summer Monsoon-EASM), an index of meteorological conditions (called PLAM, Parameter Linking Air Quality and Meteorological Elements, which is almost linearly related with aerosol pollution), and aerosol optical depth (AOD) in the middle and lower reaches of the Yangtze River (M-LYR) in central eastern China during summertime since the 1960's. During the weak monsoon years, the aerosol pollution load was heavier in the M-LYR and opposite in the strong monsoon years mainly influenced by EASM and associated maintenance position of the anti-Hadley cell around 115°E. The interdecadal changes in meteorological conditions and their associated aerosol pollution in the context of such climate change have experienced four periods since the 1960's, which were a relatively large decreased period from 1961 to 1980, a large rise between 1980 and 1999, a period of slow rise or maintenance from 1999 to 2006, and a relatively rapid rise between 2006 and 2014. Among later three pollution increased periods, about 51%, 25% and 60% of the aerosol pollution change respectively come from the contribution of worsening weather conditions, which are found to be greatly affected by changes in EASM.

RGD-modified oncolytic adenovirus-harboring shPKM2 exhibits a potent cytotoxic effect in pancreatic cancer via autophagy inhibition and apoptosis promotion.

The M2 isoform of pyruvate kinase (PKM2) is a key driver of glycolysis in cancer cells and has critical 'non-metabolic' functions in some cancers; however, the role of PKM2 in pancreatic cancer remains unclear. The aim of the current study was to elucidate the role of PKM2 in pancreatic cancer progression and the potential of PKM2 as a therapeutic target. In this study, we observed that PKM2 is highly expressed in patients with pancreatic cancer and is correlated to survival. Elevated PKM2 expression promoted cell proliferation, migration and tumor formation. The inhibition of cell growth by silencing PKM2 is caused by impairment of the autophagy process. To test the potential effects of downregulating PKM2 as a clinical therapy, we constructed an RGD-modified oncolytic adenovirus containing shPKM2 (OAd.R.shPKM2) to knock down PKM2 in pancreatic cancer cells. Cells transduced with OAd.R.shPKM2 exhibited decreased cell viability, and, in a PANC-1 xenograft model, intratumoral injection of OAd.R.shPKM2 resulted in reduced tumor growth. Furthermore, OAd.R.shPKM2 induced apoptosis and impaired autophagy in PANC-1 cells. Our results suggested that targeting PKM2 with an oncolytic adenovirus produced a strong antitumor effect, and that this strategy could broaden the therapeutic options for treating pancreatic cancer.

A Potent In Vivo Antitumor Efficacy of Novel Recombinant Type I Interferon.

Purpose: Antiproliferative, antiviral, and immunomodulatory activities of endogenous type I IFNs (IFN1) prompt the design of recombinant IFN1 for therapeutic purposes. However, most of the designed IFNs exhibited suboptimal therapeutic efficacies against solid tumors. Here, we report evaluation of the in vitro and in vivo antitumorigenic activities of a novel recombinant IFN termed sIFN-I.Experimental Design: We compared primary and tertiary structures of sIFN-I with its parental human IFNα-2b, as well as affinities of these ligands for IFN1 receptor chains and pharmacokinetics. These IFN1 species were also compared for their ability to induce JAK-STAT signaling and expression of the IFN1-stimulated genes and to elicit antitumorigenic effects. Effects of sIFN-I on tumor angiogenesis and immune infiltration were also tested in transplanted and genetically engineered immunocompetent mouse models.Results: sIFN-I displayed greater affinity for IFNAR1 (over IFNAR2) chain of the IFN1 receptor and elicited a greater extent of IFN1 signaling and expression of IFN-inducible genes in human cells. Unlike IFNα-2b, sIFN-I induced JAK-STAT signaling in mouse cells and exhibited an extended half-life in mice. Treatment with sIFN-I inhibited intratumoral angiogenesis, increased CD8+ T-cell infiltration, and robustly suppressed growth of transplantable and genetically engineered tumors in immunodeficient and immunocompetent mice.Conclusions: These findings define sIFN-I as a novel recombinant IFN1 with potent preclinical antitumorigenic effects against solid tumor, thereby prompting the assessment of sIFN-I clinical efficacy in humans. Clin Cancer Res; 23(8); 2038-49. ©2016 AACR.