Glucocorticoid-induced tumor necrosis factor receptor–related protein co-stimulation facilitates tumor regression by inducing IL-9–producing helper T cells

Kim, Il-Kyu,Kim, Byung-Seok,Koh, Choong-Hyun,Seok, Jae-Won,Park, Jun-Seok,Shin, Kwang-Soo,Bae, Eun-Ah,Lee, Ga-Eun,Jeon, Hyewon,Cho, Jaebeom,Jung, Yujin,Han, Daehee,Kwon, Byoung S,Lee, Ho-Young,Chung, Nature Publishing Group, a division of Macmillan P 2015 Nature medicine Vol.21 No.9

<P>T cell stimulation via glucocorticoid-induced tumor necrosis factor receptor (TNFR)-related protein (GITR) elicits antitumor activity in various tumor models; however, the underlying mechanism of action remains unclear. Here we demonstrate a crucial role for interleukin (IL)-9 in antitumor immunity generated by the GITR agonistic antibody DTA-1. IL-4 receptor knockout (Il4ra(-/-)) mice, which have reduced expression of IL-9, were resistant to tumor growth inhibition by DTA-1. Notably, neutralization of IL-9 considerably impaired tumor rejection induced by DTA-1. In particular, DTA-1-induced IL-9 promoted tumor-specific cytotoxic T lymphocyte (CTL) responses by enhancing the function of dendritic cells in vivo. Furthermore, GITR signaling enhanced the differentiation of IL-9-producing CD4(+) T-helper (T(H)9) cells in a TNFR-associated factor 6 (TRAF6)- and NF-kappa B-dependent manner and inhibited the generation of induced regulatory T cells in vitro. Our findings demonstrate that GITR co-stimulation mediates antitumor immunity by promoting T(H)9 cell differentiation and enhancing CTL responses and thus provide a mechanism of action for GITR agonist-mediated cancer immunotherapies.</P>

<i>In vivo</i> genotoxicity evaluation of lung cells from Fischer 344 rats following 28 days of inhalation exposure to MWCNTs, plus 28 days and 90 days post-exposure

Kim, Jin Sik,Sung, Jae Hyuck,Choi, Byung Gil,Ryu, Hyeon Yeol,Song, Kyung Seuk,Shin, Jae Hoon,Lee, Jong Seong,Hwang, Joo Hwan,Lee, Ji Hyun,Lee, Gun Ho,Jeon, Kisoo,Ahn, Kang Ho,Yu, Il Je Informa Healthcare 2014 INHALATION TOXICOLOGY Vol.26 No.4

<P>Despite their useful physico-chemical properties, carbon nanotubes (CNTs) continue to cause concern over occupational and human health due to their structural similarity to asbestos. Thus, to evaluate the toxic and genotoxic effect of multi-wall carbon nanotubes (MWCNTs) on lung cells <I>in vivo</I>, eight-week-old rats were divided into four groups (each group = 25 animals), a fresh air control (0 mg/m<SUP>3</SUP>), low (0.17 mg/m<SUP>3</SUP>), middle (0.49 mg/m<SUP>3</SUP>), and high (0.96 mg/m<SUP>3</SUP>) dose group, and exposed to MWCNTs <I>via</I> nose-only inhalation 6 h per day, 5 days per week for 28 days. The count median length and geometric standard deviation for the MWCNTs determined by TEM were 330.18 and 1.72 nm, respectively, and the MWCNT diameters ranged from 10 to 15 nm. Lung cells were isolated from five male and five female rats in each group on day 0, day 28 (only from males) and day 90 following the 28-day exposure. The total number of animals used was 15 male and 10 female rats for each concentration group. To determine the genotoxicity of the MWCNTs, a single cell gel electrophoresis assay (Comet assay) was conducted on the rat lung cells. As a result of the exposure, the olive tail moments were found to be significantly higher (<I>p</I> < 0.05) in the male and female rats from all the exposed groups when compared with the fresh air control. In addition, the high-dose exposed male and middle and high-dose exposed female rats retained DNA damage, even 90 days post-exposure (<I>p</I> < 0.05). To investigate the mode of genotoxicity, the intracellular reactive oxygen species (ROS) levels and inflammatory cytokine levels (TNF-α, TGF- β, IL-1, IL-2, IL-4, IL-5, IL-10, IL-12 and IFN-γ) were also measured. For the male rats, the H<SUB>2</SUB>O<SUB>2</SUB> levels were significantly higher in the middle (0 days post-exposure) and high- (0 days and 28 days post-exposure) dose groups (<I>p</I> < 0.05). Conversely, the female rats showed no changes in the H<SUB>2</SUB>O<SUB>2</SUB> levels. The inflammatory cytokine levels in the bronchoalveolar lavage (BAL) fluid did not show any statistically significant difference. Interestingly, the short-length MWCNTs deposited in the lung cells were persistent at 90 days post-exposure. Thus, exposing lung cells to MWCNTs with a short tube length may induce genotoxicity.</P>

GM-CSF Promotes Antitumor Immunity by Inducing Th9 Cell Responses

Kim, Il-Kyu,Koh, Choong-Hyun,Jeon, Insu,Shin, Kwang-Soo,Kang, Tae-Seung,Bae, Eun-Ah,Seo, Hyungseok,Ko, Hyun-Ja,Kim, Byung-Seok,Chung, Yeonseok,Kang, Chang-Yuil American Association for Cancer Research 2019 Cancer immunology research Vol.7 No.3

<P>Granulocyte-macrophage colony-stimulating factor (GM-CSF) functions as an adjuvant for antitumor immunity through an unclear mechanism. By activating monocyte-derived dendritic cells, GM-CSF induces Th9 development and IL9 production, which facilitates antitumor cytotoxic T lymphocyte responses.</P><P>GM-CSF as an adjuvant has been shown to promote antitumor immunity in mice and humans; however, the underlying mechanism of GM-CSF–induced antitumor immunity remains incompletely understood. In this study, we demonstrate that GM-CSF potentiates the efficacy of cancer vaccines through IL9-producing Th (Th9) cells. GM-CSF selectively enhanced Th9 cell differentiation by regulating the COX2–PGE<SUB>2</SUB> pathway while inhibiting the differentiation of induced regulatory T (iTreg) cells <I>in vitro</I> and <I>in vivo</I>. GM-CSF–activated monocyte-derived dendritic cells converted tumor-specific nai¨ve Th cells into Th9 cells, and delayed tumor growth by inducing antitumor CTLs in an IL9-dependent manner. Our findings reveal a mechanism for the adjuvanticity of GM-CSF and provide a rationale for the use of GM-CSF in cancer vaccines.</P>

Activation of NKT Cells in an Anti-PD-1–Resistant Tumor Model Enhances Antitumor Immunity by Reinvigorating Exhausted CD8 T Cells

Bae, Eun-Ah,Seo, Hyungseok,Kim, Byung-Seok,Choi, Jeongwon,Jeon, Insu,Shin, Kwang-Soo,Koh, Choong-Hyun,Song, Boyeong,Kim, Il-Kyu,Min, Byung Soh,Han, Yoon Dae,Shin, Sang Joon,Kang, Chang-Yuil American Association for Cancer Research 2018 Cancer Research Vol.78 No.18

<P>These findings provide mechanistic insights into the application of NKT cell stimulation as a potent adjuvant for immunotherapy against advanced cancer.</P><P>PD-1–based cancer immunotherapy is a successful example of immune checkpoint blockade that provides long-term durable therapeutic effects in patients with cancer across a wide spectrum of cancer types. Accumulating evidence suggests that anti-PD-1 therapy enhances antitumor immunity by reversing the function of exhausted T cells in the tumor environment. However, the responsiveness rate of patients with cancer to anti-PD-1 therapy remains low, providing an urgent need for optimization and improvement. In this study, we designed an anti-PD-1–resistant mouse tumor model and showed that unresponsiveness to anti-PD-1 is associated with a gradual increase in CD8 T-cell exhaustion. We also found that invariant natural killer T cell stimulation by the synthetic ligand α-galactosylceramide (αGC) can enhance the antitumor effect in anti-PD-1–resistant tumors by restoring the effector function of tumor antigen–specific exhausted CD8 T cells. IL2 and IL12 were among the cytokines produced by αGC stimulation critical for reinvigorating exhausted CD8 T cells in tumor-bearing mice and patients with cancer. Furthermore, we observed a synergistic increase in the antitumor effect between αGC-loaded antigen-presenting cells and PD-1 blockade in a therapeutic murine tumor model. Our study suggests NKT cell stimulation as a promising therapeutic strategy for the treatment of patients with anti-PD-1–resistant cancer.</P><P><B>Significance:</B> These findings provide mechanistic insights into the application of NKT cell stimulation as a potent adjuvant for immunotherapy against advanced cancer. <I>Cancer Res; 78(18); 5315–26. ©2018 AACR</I>.</P>

국지풍 모델과 2차 모멘트법을 이용한 대기오염 물질의 이류확산 수치모의

전병일 新羅大學校 1999 論文集 Vol.47 No.-

The two-stage numerical model was used to study the relation bitween three-dimensional local wind model,adviction/diffusion model of second moment method in south-eastern coastal area for Korean peninsula.The first stage is three dimensional time-dependent local wind model which gives the wind field and vertical diffusion coefficient. The scond stage is advection/diffusion model(scond moment method) which uses the results of the first stage as input data. First, wind fields on Korean peninsula for none synoptic scale wind showed typical land and sea breeze cirulation, and the emitted particles were transported by sea breeze for daytime, emissions return to sea by land breeze for nighttime. Hence, more detailed work needs to be carried out in the future.

낙동강 하구둑 축조에 따른 기상환경 변화

전병일 新羅大學校 1998 論文集 Vol.46 No.-

This study considered the change of meteorological environment according to construction of Nakdong-river estuary barrage using to Kimhae air force meteorological data. The artificial lake cause frequent radiation fog and visibility degradation on marginal region. The mean temperature at the time after the construction(1988∼1996) of estuary barrage was 13.9℃ while before the construction(1975∼1983) was 13.7℃. The minimum temperature after the construction was 9.4℃ while before the construction was 9.3℃. The annual mean precipitation after the construction of estuary barrage was 1.297mm while before the construction was 1.356mm. The change of relative humidity after the construction increased 8% annually than that of the percent before the construction. The day of radiation fog after the construction was 84.4 days while before the construction was 62.3 days. The fog occurrence rate according to construction of estuary barrage increased obviously.

강원도 태백시 산사면에서의 하계 야간기상특성 조사

전병일,이영미 新羅大學校 2001 論文集 Vol.50 No.-

A series of meteorological observation using automation weather station(AWS) carried out to investigate characteristics of nocturnal meteorological parameters for 24∼25 June 2000 at lower site(Choojeon station) and upper site(Ssarijae). Taebaek city mountain slope in Kangwon-Province. Dry temperature at lower site was higher than upper site from sunset 24 to sunrise 25. June. Contrary of dry temperature, relative humidity of lower site was lower than upper site for night-time. Wind direction at lower site from beginning of observation to 1200∼0300LST 25, June were southeasterly(SE), after the time were northwesterly(NW) or north(N), so mountain-valley wind as local wind was showed. Wind speed at two site from sunset to 2200LST 24, June was about 1.0m/s, except for the calm as below 0.5m/s.

부산지역 흐린 날의 고농도 오존 발생의 사례 연구

전병일 신라대학교 자연과학연구소 2003 自然科學論文集 Vol.11 No.-

This study was carried out to survey the high ozone episode for cloudy day in Busan. The selected day was July 18, 1999 which recorded exceed to 12ppb/hr at 3 station in Busan. According to increase sunshine and radiation after 12LST, the high ozone concentration increased fast in Busan metropolitan area. Thick cloud and variable wind made weak ozone concentration during morning hour. And increase of ozone concentration by revolution of mixed layer for morning hour did not occur in this case study day. Photochemical reaction by strong radiation after 1100LST made sharp increase rate of ozone concentration(50ppb/hr).

2002년 11월의 황사 발생시 부산지역의 PM10 농도에 대한 사례 연구

전병일 신라대학교 자연과학연구소 2003 自然科學論文集 Vol.12 No.-

This study was performed to research the characteristics of PM10 for Asian dust of November, 2002 at Busan. Yellow Sand frequency during 15 years(1988-2002) at Busan showed maximum in April(49%), next to March(26%), May(14%). According to result of 850hPa weather map and backward isentropic trajectory, this event originated from the Northwestern district of China. And four mode was found in time series of PM10 concentration, primary peak showed the maximum hourly concentration at all station. Lasted time from primary peak to secondary peak was about 3 hours, between secondary peak and third peak was 9 hours at Busan, The traveling time between occurrence of Asian dust the finding of it was 10 hours at Busan.

부산 해안지역의 고농도 오존 발생 특성에 관한 연구

전병일 한국환경과학회 2000 한국환경과학회지 Vol.9 No.4

This study was conducted to investigate the characteristics of surface ozone concentration and occurrence of high ozone concentration using hourly ozone, nitrogen dioxide and meteorological data for 1997∼1998 in Pusan coastal area. Monthly mean ozone concentration was the highest at Dongsamdong in Spring(35.4ppb), at Kwangbokdong in Fall(25.lppb) and the lowest Dongsamdong(22.2ppb) and Kwangbokdong(16.0ppb) in Winter. Relative standard deviation indicating clearness of observation site was 0.42 at Dongsamdong and 0.49 at Kwangbokdong that is similar to urban area. The diurnal variation of ozone concentration of Dongsamdong and Kwangbokdong showed maximum at 1500∼1600LST and minimum 0700∼0800LST that typical pattern of ozone concentration. In ozone episode period(Sept. 10∼15, 1998), diurnal change of ozone concentration was very high, and ozone concentration was related to meteorological parameters such as temperature, relative humidity, wind speed, cloud amount and radiation on a horizontal surface. During the episode days peak ozone concentrations are much higher than the normal values, wind speeds are always lower, and solar radiation is high with the exception of the September episode.