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Although immune-related adverse events (irAEs) of treatment with immune-checkpoint inhibitors may be due to cellular immunity mediated by T lymphocytes, their pathogenesis has remained unknown. Here we collected bronchoalveolar lavage fluid (BALF) from a cancer patient with nivolumab-induced pneumonitis and isolated mononuclear cells for next-generation sequencing of the complementarity-determining region of the T cell receptor (TCR) β chain. Mononuclear cells in peritumoral pleural effusion isolated from the patient were similarly analyzed, and the results obtained for the two specimens were compared. A substantial number of TCRβ clones in BALF were also identified among lymphocytes in the peritumoral pleural effusion. Such a correlation was not apparent between TCRβ clones in BALF and those in peripheral blood. Moreover, many tumor-associated clones with a read frequency of ≥0.10% were also present in BALF. Our data suggest that irAEs might be induced by drug-activated lymphocytes originating from tumor tissue. Deep sequencing will thus be indispensable for investigations of the immune-based pathogenesis of, and the development of optimal treatments for, irAEs.

// Irina N. Mikhaylova 1 , Irina Zh. Shubina 1 , George Z. Chkadua 1 , Natalia N. Petenko 1 , Lidia F. Morozova 1 , Olga S. Burova 1 , Robert Sh. Beabelashvili 2 , Kermen A. Parsunkova 3 , Natalia V. Balatskaya 4 , Dmitrii K. Chebanov 5 , Vadim I. Pospelov 6 , Valeria V. Nazarova 1 , Anastasia S. Vihrova 1 , Evgeny A. Cheremushkin 1 , Alvina A. Molodyk 1 , Mikhail V. Kiselevsky 1 and Lev V. Demidov 1 1 N.N. Blokhin Russian Cancer Research Center, Moscow, Russia 2 Laboratory of Genetic Engineering, Institute of Experimental Cardiology, Russian Cardiological Research and Production Complex, Moscow, Russia 3 Diagnostic Laboratory Clinical Center “Optimum”, Sochi, Russia 4 Department of Immunology and Virology, Moscow Helmholtz Research Institute of Eye Diseases, Moscow, Russia 5 RUDN University, Moscow, Russia 6 “Genetic Technologies and Analyses”, Moscow, Russia Correspondence to: Irina Zh. Shubina, email: irinashubina@mail.ru Keywords: cancer vaccine therapy; melanoma; predictive markers; B2-microglobulin Received: September 04, 2017 Accepted: March 22, 2018 Published: May 11, 2018 ABSTRACT Immunotherapy has shown promising results in a variety of cancers, including melanoma. However, the responses to therapy are usually heterogeneous, and understanding the factors affecting clinical outcome is still not achieved. Here, we show that immunological monitoring of the vaccine therapy for melanoma patients may help to predict the clinical course of the disease. We studied cytokine profile of cellular Th1 (IL-2, IL-12, IFN-γ) and humoral Th2 (IL-4, IL-10) immune response, vascular endothelial growth factor (VEGFA), transforming growth factor-β 2 (TGF-β 2), S100 protein (S100A1B and S100BB), adhesion molecule CD44 and serum cytokines β2-microglobulin to analyze different peripheral blood mononuclear cell subpopuations of patients treated with dendritic vaccines and/or cyclophosphamide in melanoma patients in the course of adjuvant treatment. The obtained data indicate predominance of cellular immunity in the first adjuvant group of patients with durable time to progression and shift to humoral with low cellular immunity in patients with short-term period to progression (increased levels of IL-4 and IL- 10). Beta-2 microglobulin was differentially expressed in adjuvant subgroups: its higher levels correlated with shorter progression-free survival and the total follow-up time. Immunoregulatory index was overall higher in patients with disease progression compared to the group of patients with no signs of disease progression.

// Hongrui Guo 1, * , Ping Kuang 1, * , Qin Luo 1, * , Hengmin Cui 1, 2 , Huidan Deng 1 , Huan Liu 1 , Yujiao Lu 1 , Jing Fang 1, 2 , Zhicai Zuo 1, 2 , Junliang Deng 1, 2 , Yinglun Li 1, 2 , Xun Wang 1, 2 and Ling Zhao 1, 2 1 College of Veterinary Medicine, Sichuan Agricultural University, Ya’an 625014, China 2 Key Laboratory of Animal Diseases and Environmental Hazards of Sichuan Province, Sichuan Agriculture University, Ya’an 625014, China * These authors have contributed equally to this work Correspondence to: Hengmin Cui, email: cui580420@sicau.edu.cn Keywords: NaF, blood, cellular immunity, humoral immunity, mice Received: March 21, 2017 Accepted: July 19, 2017 Published: August 10, 2017 ABSTRACT Exposure to high fluorine can cause toxicity in human and animals. Currently, there are no systematic studies on effects of high fluorine on blood cellular immunity and humoral immunity in mice. We evaluated the alterations of blood cellular immunity and humoral immunity in mice by using flow cytometry and ELISA. In the cellular immunity, we found that sodium fluoride (NaF) in excess of 12 mg/Kg resulted in a significant decrease in the percentages of CD3 + , CD3 + CD4 + , CD3 + CD8 + T lymphocytes in the peripheral blood. Meanwhile, serum T helper type 1 (Th1) cytokines including interleukin (IL)-2, interferon (IFN)-γ, tumor necrosis factor (TNF), and Th2 cytokines including IL-4, IL-6, IL-10, and Th17 cytokine (IL-17A) contents were decreased. In the humoral immunity, NaF reduced the peripheral blood percentages of CD19 + B lymphocytes and serum immunoglobulin A (IgA), immunoglobulin G (IgG) and immunoglobulin M (IgM). The above results show that NaF can reduce blood cellular and humoral immune function in mice, providing an excellent animal model for clinical studies on immunotoxicity-related fluorosis.

// Mingrong Cheng 1, 2, * , Weiping Zhu 3, 5, * , Qing Li 4, * , Dejian Dai 2 and Yiming Hou 5 1 Department of General Surgery, Pudong New Area District Zhoupu Hospital, Shanghai 201318, China 2 Department of General Surgery, Shanghai Tianyou Hospital, Tongji University, Shanghai 200000, China 3 Department of Hepatic Surgery, Fudan University Shanghai Cancer Center, Shanghai Medical College, Fudan University, Shanghai 200032, China 4 Department of Medical Clinic, Pujiang Community Health Service Center, Shanghai 201112, China 5 Department of General Surgery, Shanghai Fifth People’s Hospital, Fudan University, Shanghai 200240, China * These authors have contributed equally to this work Correspondence to: Weiping Zhu, email: wpzhush@hotmail.com Dejian Dai, email: daidejian@hotmail.com Keywords: biotin chitosan, curative effect, drug delivery system, liver cancer, nanoparticles Received: August 08, 2016 Accepted: June 02, 2017 Published: July 10, 2017 ABSTRACT The present study investigated the synthesis of biotinylated chitosan (Bio-CS) from chitosan using a nanomaterial skeleton with biotin and the successful targeting of the formulation in liver cancer cells. Bio-CS was validated by fourier transformed infrared spectroscopy and hydrogen -1 nuclear magnetic resonance spectroscopy. Bio-CS and plasmid DNA were used to construct Bio-CS/plasmid DNA nanoparticles according to the optimal molar ratio of 1:1 and the optimal pH-value of 5.5. Under these conditions, the parameters mean particle size, potential, encapsulation rate and drug loading, were 82.9 nm, +21.8 mV, 85.7% and 35.4%, respectively. Bio-CS exhibited an apparent liver cancer targeting effect in vitro and in vivo , as demonstrated by confocal laser scanning, green fluorescent protein transfection, and in vivo imaging assays. In addition, the Bio-CS/plasmid DNA nanoparticles significantly increased the survival period of the orthotropic liver cancer mouse model compared with the plasmid DNA, with no apparent side effects on the cells. Bio-CS nanomaterials stimulated an immune response in hepatoma cells via increased expression of GM-CSF, IL-21 and Rae-1 markers. The data suggest that Bio-CS increased the inhibition of liver cancer cell proliferation in vitro and the activation of the cellular immunity in vivo .

// Wei Wang 1 , Ge Shen 1 , Shikai Wu 1 , Shiping Song 1 , Yanli Ni 1 , Zhuoyao Suo 1 , Xiangying Meng 1 , Dan Li 1 , Lin Zhou 1 , Rimin Hao 1 , Yaowei Zhao 1 , Li Bai 1 , Lili Hou 1 , Bing Liu 1 and Guangxian Liu 1 1 Cancer Therapy Center, Affiliated Hospital of The Academy of Military Medical Sciences, Beijing 100071, China Correspondence to: Guangxian Liu, email: liugx270@hotmail.com Bing Liu, email: bingliu17@yahoo.com Keywords: PD-1, peripheral immune cells, immunomodulation, radiation therapy, cancer Received: June 15, 2016 Accepted: January 16, 2017 Published: February 02, 2017 ABSTRACT Immune checkpoint inhibitors that block the PD-1/PD-L1 signaling pathway have been used to treat a wide variety of cancers. Although results have been promising, significant inter-individual and inter-tumor variability has been observed. It is believed that better clinical outcome could be achieved if the treatment was individually designed based on the functional status of the PD-1/PD-L1 signaling and the cellular immunity. In this study, we analyzed the mRNA expression of PD-1 and other immunomodulatory genes in peripheral blood from cancer patients, and immunomodulatory gene expression during radiotherapy and immunomodulation therapy with cytokines. Our results show that the PD-1 mRNA expression is significantly increased in peripheral blood in cancer patients. Anti-cancer treatments can significantly modulate the PD-1 expression, but this is largely dependent on the initial immune status. Moreover, the PD-1 expression on peripheral lymphocytes can be immunoactivation-derived. These results suggest that the regulation and expression pattern of PD-1/PD-L1 signal is complicated which will influence the effect of blockade of the PD-1/PD-L1 signaling pathway for cancer treatment. Through combined analysis of PD-1, CTLA-4, and other immune markers in peripheral blood, we may accurately evaluate the functional status of PD-1/PD-L1 signaling and cellular immunity, thereby providing clues for guiding anti-PD-1 or anti-PD-L1 treatment.

// So Young Kim 1, * , Dongxu Kang 1, 2, * , Hye Jin Choi 3 , Yeonsoo Joo 1, 4 , Joo-Hang Kim 5 , Jae J. Song 1, 4 1 Institute for Cancer Research, Yonsei University College of Medicine, Seoul, Korea 2 Department of Oncology, Affiliated Hospital of Yanbian University, Yanji, Jilin Province, P.R. China 3 Department of Internal Medicine, Yonsei University College of Medicine, Seoul, Korea 4 Severance Biomedical Science Institute, Yonsei University College of Medicine, Seoul, Korea 5 CHA Bundang Medical Center, CHA University, Seongnam, Korea * These authors have contributed equally to this work Correspondence to: Joo-Hang Kim, email: kim123@cha.ac.kr Jae J. Song, email: jjs109@yuhs.ac Keywords: oncolytic adenovirus, MART1, DNA vaccine, GM-CSF, TGF-β2 Received: June 20, 2016 Accepted: December 31, 2016 Published: February 02, 2017 ABSTRACT A successful DNA vaccine for the treatment of tumors should break established immune tolerance to tumor antigen. However, due to the relatively low immunogenicity of DNA vaccines, compared to other kinds of vaccines using live virus or protein, a recombinant viral vector was used to enhance humoral and cellular immunity. In the current study, we sought to develop a novel anti-cancer agent as a complex of DNA and oncolytic adenovirus for the treatment of malignant melanoma in the C57BL/6 mouse model. MART1, a human melanoma-specific tumor antigen, was used to induce an increased immune reaction, since a MART1-protective response is required to overcome immune tolerance to the melanoma antigen MelanA. Because GM-CSF is a potent inducer of anti-tumor immunity and TGF-β2 is involved in tumor survival and host immune suppression, mouse GM-CSF (mGM-CSF) and shRNA of mouse TGF-β2 (shmTGF-β2) genes were delivered together with MART1 via oncolytic adenovirus. MART1 plasmid was also used for antigen-priming. To compare the anti-tumor effect of oncolytic adenovirus expressing both mGM-CSF and shmTGF-β2 (Ad GshT ) with that of oncolytic adenovirus expressing mGM-CSF only (Ad G ), each virus was intratumorally injected into melanoma-bearing C57BL/6 mice. As a result, mice that received Ad GshT showed delayed tumor growth than those that received Ad G . Heterologous prime-boost immunization was combined with oncolytic Ad GshT and MART1 expression to result in further delayed tumor growth. This regression is likely due to the following 4 combinations: MART1-derived mouse melanoma antigen-specific immune reaction, immune stimulation by mGM-CSF/shmTGF-β2, tumor growth inhibition by shmTGF-β2, and tumor cell-specific lysis via an oncolytic adenovirus. Immune activation was mainly induced by mature tumor-infiltrating dendritic cell (TIDC) and lowered regulatory T cells in tumor-infiltrating lymphocytes (TIL). Taken together, these findings demonstrate that human MART1 induces a mouse melanoma antigen-specific immune reaction. In addition, the results also indicate that combination therapy of MART1 plasmid, together with an oncolytic adenovirus expressing MART1, mGM-CSF, and shmTGF-β2, is a promising candidate for the treatment of malignant melanoma.

// Chao Liu 1 , Shikai Wu 1 , Xiangying Meng 1 , Guangxian Liu 2 , Dongmei Chen 1 , Yang Cong 1 , Ge Shen 1 , Bing Sun 1 , Wei Wang 2 , Qian Wang 1 , Hongjun Gao 3 and Xiaoqing Liu 3 1 Department of Radiation Oncology, Affiliated Hospital of Academy of Military Medical Sciences, Beijing, China 2 Cancer Therapy Center, Affiliated Hospital of Academy of Military Medical Sciences, Beijing, China 3 Department of Lung Cancer, Affiliated Hospital of Academy of Military Medical Sciences, Beijing, China Correspondence to: Shikai Wu, email: // Keywords : T cells; lymphocyte subsets; stereotactic body radiation therapy; non-small cell lung cancer; immunotherapy Received : December 19, 2016 Accepted : January 27, 2017 Published : February 09, 2017 Abstract Background: Studies increasingly focus on the impact of radiotherapy on immunity; however, the role of peripheral cellular immunity prior to radiotherapy in cancer patients remains largely unknown. In this study, we investigated the predictive roles of lymphocyte subsets on tumor progression in non-small cell lung cancer (NSCLC) patients undergoing radiotherapy, and their expression in NSCLC patients at first relapse. Methods: We enrolled 70 NSCLC patients and 14 age- and sex-matched healthy donors and tested the lymphocyte subsets in their peripheral blood by flow cytometry. Among them, 40 newly diagnosed patients received radiotherapy and were enrolled to investigate the predictive value of lymphocyte subsets on tumor progression after radiotherapy by uni- and multivariate analyses; 30 patients at first relapse were included to evaluate the differences of lymphocyte subsets between them and first diagnosed patients and healthy volunteers. Results: Increased proportions of regulatory T cells, CD8+ T cells, and CD8+CD28- T cells and decreased CD4+ T cells and CD4/CD8 ratios were observed in NSCLC patients at first relapse compared to newly diagnosed patients. In the 40 first diagnosed patients undergoing radiotherapy, uni- and multivariate analyses showed that increased level of regulatory T cells correlated with poor progression-free survival (hazard ratio = 2.55 and 3.76, P = 0.022 and 0.010, respectively). Conclusions: Peripheral regulatory T cells were increased and independently predict tumor progression in NSCLC patients undergoing radiotherapy, suggesting the promising combination of radiotherapy and immunotherapy.

// Ping Kuang 1, * , Huidan Deng 1, * , Hengmin Cui 1, 2 , Lian Chen 1 , Jing Fang 1, 2 , Zhicai Zuo 1, 2 , Junliang Deng 1, 2 , Xun Wang 1, 2 , Ling Zhao 1, 2 1 College of Veterinary Medicine, Sichuan Agricultural University, Ya’an 625014, China 2 Key Laboratory of Animal Diseases and Environmental Hazards of Sichuan Province, Sichuan Agricultural University, Ya’an 625014, China * These authors contributed equally to this work Correspondence to: Hengmin Cui, email: cui580420@sicau.edu.cn Keywords: NaF, growth index, T and B-cell, cytokine, cell cycle Received: November 07, 2016 Accepted: December 07, 2016 Published: December 16, 2016 ABSTRACT At present, very limited studies focus on the toxic effect of sodium fluoride (NaF) on splenic development of human and animals in vivo . This study was firstly designed to evaluate the toxic effects of NaF on the splenic development of mice in vivo by observing histopathological lesions, changes of splenic growth index (GI), T and B cells, immunoglobulin A (IgA), immunoglobulin G (IgG) and immunoglobulin M (IgM) contents, cytokine protein expression levels, and cell cycle and cyclins/cdks protein expression levels using the methods of pathology, flow cytometry (FCM), western blot (WB), and enzyme-linked immunosorbent assay (ELISA). A total of 240 ICR mice were equally allocated into four groups with intragastric administration of distilled water in the control group and 12, 24, 48 mg/kg NaF solution in the experimental groups for 42 days. The results showed that NaF in 12 mg/kg and over caused the toxic effects on splenic development, which was characterized by reducing growth index and lymphocytes in the white and red pulp histopathologically, increasing cell percentages of the G0/G1 phase and decreasing cell percentages of the S phase, and reducing T cells and B cells as well as IgA, IgG, and IgM contents when compared with those in the control group. Concurrently, cytokines including interleukin-2 (IL-2), transforming growth factor beta (TGF-β), tumor necrosis factor alpha (TNF-α), interferon gamma (IFN-γ) and cyclin (E/D and CDK2/4) protein expression levels were markedly decreased ( P < 0.05 or P < 0.01), and interleukin-10 (IL-10) protein expression levels were significantly increased ( P < 0.05 and P < 0.01) in the three NaF-treated groups. Toxic effects finally impaired the splenic cellular immunity and humoral immunity due to the reduction of T and B cell population and activity. Cell cycle arrest is the molecular basis of NaF-caused toxic effects on the splenic development.

// Erlong Wang 1,* , Bo Long 1,* , Kaiyu Wang 1,2 , Jun Wang 1 , Yang He 1 , Xingli Wang 1 , Qian Yang 1 , Tao Liu 1 , Defang Chen 3 , Yi Geng 1,2 , Xiaoli Huang 3 , Ping Ouyang 1 and Weimin Lai 1 1 Department of Basic Veterinary, College of Veterinary Medicine, Sichuan Agricultural University, Chengdu, Sichuan, China 2 Key Laboratory of Animal Disease and Human Health of Sichuan Province, Sichuan Agricultural University, Chengdu, Sichuan, China 3 Department of Aquaculture, College of Animal Science and Technology, Sichuan Agricultural University, Chengdu, Sichuan, China * These authors have contributed equally to this work Correspondence to: Kaiyu Wang, email: // Keywords : aquaculture, bacterial diseases, DNA vaccine, interleukin-8, molecular adjuvant, Immunology and Microbiology Section, Immune response, Immunity Received : August 20, 2016 Accepted : November 15, 2016 Published : November 30, 2016 Abstract DNA vaccines had been widely used in animal models against various viral infections, while it was not so convincing for many infectious diseases especially bacterial disease in aquaculture. Interleukin-8(IL-8) as one of the CXC chemokines, its immunological role and adjuvant potential which had been proved in mammals were rarely reported in fish species. In this study, recombination plasmid pcDNA3.1/IL-8(pcIL-8) was conducted and the capacity of IL-8 as molecular adjuvant was explored from several aspects by co-injecting with a DNA vaccine encoding α-enolase(pcENO) against Streptococcus iniae infection in channel catfish. The results suggested that co-injection of pcIL-8 with DNA vaccine increased the innate immunity and specific antibody levels, as well as increased the immune-related genes involving in pro-inflammatory response, humoral and cellular immunity. Moreover, pcIL-8 enhanced the immunoprotection of pcENO with the relative percent survival(RPS) of 60% to 80% against S.iniae infection at 4 week post vaccination(p.v.), with the significantly higher RPS of 73.33% in pcENO+pcIL-8 group compared with that of pcENO alone(53.33%) at challenge test of 8 weeks p.v. Taken together, these results indicate pcIL-8 as a molecular adjuvant co-injected with DNA vaccine not only improves the immunoprotection but also maintains long period of immunity for channel catfish against S.iniae infection. Our study signifies that IL-8 holds promise to serve as a potential adjuvant in DNA vaccines against bacterial infections for long time.

// Yanxia Lu 1 , Crystal Tze Ying Tan 2 , Ma Shwe Zin Nyunt 3 , Esther Wing Hei Mok 2 , Xavier Camous 2 , Hassen Kared 2 , Tamas Fulop 4 , Liang Feng 5 , Tze Pin Ng 3,* and Anis Larbi 2,4* 1 Department of Clinical Psychology and Psychiatry/School of Public Health, Zhejiang University College of Medicine, Hangzhou, China 2 Singapore Immunology Network (SIgN), Agency for Science, Technology and Research (A*STAR), Singapore 3 Gerontology Research Programme, Department of Psychological Medicine, Yong Loo Lin School of Medicine, National University of Singapore, Singapore 4 Geriatrics Division, Department of Medicine, Research Center on Aging, University of Sherbrooke, Sherbrooke, Quebec, Canada 5 Graduate Medical School, Duke-National University of Singapore, Singapore * These authors have contributted equally to this work Correspondence to: Anis Larbi, email: // Keywords : inflammation; immunosenescence; frailty risk; T cell subsets; B cells; Gerotarget Received : November 18, 2015 Accepted : April 10, 2016 Published : April 22, 2016 Abstract Chronic systematic inflammation and reduced immune system fitness are considered potential contributing factors to the development of age-related frailty, but the underlying mechanisms are poorly defined. This exploratory study aimed to identify frailty-related inflammatory markers and immunological phenotypes in a cohort of community-dwelling adults aged ≥ 55 years. Frailty was assessed using two models, a Frailty Index and a categorical phenotype, and correlated with levels of circulating immune biomarkers and markers of senescence in immune cell subsets. We identified eight serological biomarkers that were associated with frailty, including sgp130, IL-2Rα, I-309, MCP-1, BCA-1, RANTES, leptin, and IL-6R. Frailty Index was inversely predicted by the frequency of CD3+, CD45RA+, and central memory CD4 cells, and positively predicted by the loss of CD28 expression, especially in CD8+ T cells, while frailty status was predicted by the frequency of terminal effector CD8+ T cells. In γ/δ T cells, frailty was negatively associated with CD27, and positively associated with IFNγ+TNFα- secretion by γ/δ2+ cells and IFNγ-TNFα+ secretion by γ/δ2- cells. Increased numbers of exhausted and CD38+ B cells, as well as CD14+CD16+ inflammatory monocytes, were also identified as frailty-associated phenotypes. This pilot study supports an association between inflammation, cellular immunity, and the process of frailty. These findings have significance for the early identification of frailty using circulating biomarkers prior to clinical manifestations of severe functional decline in the elderly.

Tumor necrosis factor-α induced protein 8 like-2 (TNFAIP8L2, TIPE2) is a lately discovered negative regulator of innate immunity and cellular immunity. The present study was designed to investigate whether naturally occurring dendritic cells (DCs) could express TIPE2 mRNA/protein and its potential significance. Expressions of co-stimulatory molecules on DC surface and cytokines were analyzed to assess the functional role of TIPE2 in controlling DC maturation as well as activation. The activated DCs were assessed for their capacity to stimulate the proliferation and differentiation of T cells. It was found that TIPE2 was a cytoplasmic protein expressed in DCs, and the percentage of DCs which expressed co-stimulatory molecules and cytokines were obviously up-regulated when TIPE2 gene silenced by siRNA in vitro and in vivo. DCs undergone TIPE2 knockdown were found to promote the maturation of DCs, T-cell proliferation as well as differentiation, and they were significantly elevated IL-2 level and intranuclear NF-AT activation. Conversely, in over-expressing TIPE2 DC cells, it could inhibit T-cell proliferation and differentiation, and markedly down-regulate IL-2 expression and intranuclear NF-AT activation after scald injury. The results suggested that TIPE2 appeared to be a critical immunoregulatory molecule which affected DC maturation and subsequent T-cell mediated immunity.

// Qing-Kun Song 1, * , Jun Ren 1, 2, 3, * , Xin-Na Zhou 1, 2 , Xiao-Li Wang 1, 2 , Guo-Hong Song 2 , Li-Jun Di 2 , Jing Yu 2 , Amy Hobeika 3 , Michael A. Morse 4 , Yan-Hua Yuan 1 , Hua-Bing Yang 1 , Herbert Kim Lyerly 3 1 Beijing Key Laboratory of Therapeutic Cancer Vaccines, Capital Medical University Cancer Center, Beijing Shijitan Hospital, Beijing 10038, China 2 Department of Medical Oncology, Peking University Cancer Hospital & Institute, Beijing 100142, China 3 Department of Surgery, Duke University Medical Center, Durham, NC 27710, United States 4 Department of Medicine, Duke University Medical Center, Durham, NC 27710, United States * These authors have contributed equally to this work Correspondence to: Jun Ren, e-mail: jun.ren@duke.edu Herbert Kim Lyerly, e-mail: kim.lyerly@duke.edu Keywords: CD4 + CD25 + T lymphocyte, early stage breast cancer, triple negative breast cancer, prognosis, adoptive cell therapy Received: June 16, 2015 Accepted: September 07, 2015 Published: October 05, 2015 ABSTRACT Objective: This study aimed to assess the prognostic value of CD4 + CD25 + T lymphocyte in peripheral blood among breast cancer patients treated with adoptive T lymphocytes immunotherapy. Methods: 217 patients participated in the follow-up study. CD4 + CD25 + proportion was measured by flow cytometry in peripheral T cells. The median survival was estimated by Kaplan-Meier curve, Log-rank test and Cox hazard proportion regression model, between groups of CD4 + CD25 + proportion more than 5% and less than or equal to 5% in peripheral T cells. Results: Peripheral CD4 + CD25 + T lymphocytes had not a relationship with progression-free survival. It was featured that above 5% peripheral CD4 + CD25 + proportion of T cells was related with the median overall survival by a shorten of 51 months ( p < 0.05) with the HR 1.65 (95%CI 1.04, 2.62). Above 5% CD4 + CD25 + proportion of T cells produced the HR to be 1.76 (95%CI 1.07, 2.87) In stage 0-II patients, and 3.59 (95%CI 1.05, 12.29) in triple negative breast cancer patients. Conclusion: Cellular immunity restoration recovered by adoptive T cell infusions which resulted in less proportion of peripheral CD4 + CD25 + T lymphocytes could be a potential prognostic indicator among early stage and triple negative patients.

Successful therapeutic options remain elusive for pancreatic cancer. The exquisite sensitivity and specificity of humoral and cellular immunity may provide therapeutic approaches if antigens specific for pancreatic cancer cells can be identified. Here we characterize SAS1B (ovastacin, ASTL, astacin-like), a cancer-oocyte antigen, as an attractive immunotoxin target expressed at the surface of human pancreatic cancer cells, with limited expression among normal tissues. Immunohistochemistry shows that most pancreatic cancers are SAS1Bpos (68%), while normal pancreatic ductal epithelium is SAS1Bneg. Pancreatic cancer cell lines developed from patient-derived xenograft models display SAS1B cell surface localization, in addition to cytoplasmic expression, suggesting utility for SAS1B in multiple immunotherapeutic approaches. When pancreatic cancer cells were treated with an anti-SAS1B antibody-drug conjugate, significant cell death was observed at 0.01-0.1 μg/mL, while SAS1Bneg human keratinocytes were resistant. Cytotoxicity was correlated with SAS1B cell surface expression; substantial killing was observed for tumors with low steady state SAS1B expression, suggesting a substantial proportion of SAS1Bpos tumors can be targeted in this manner. These results demonstrate SAS1B is a surface target in pancreatic cancer cells capable of binding monoclonal antibodies, internalization, and delivering cytotoxic drug payloads, supporting further development of SAS1B as a novel target for pancreatic cancer.

Possible risk mediators in primary dengue virus (DenV) infection that favor secondary DenV infection to life-threatening dengue hemorrhagic fever (DHF) and shock syndrome (DSS) via antibody-dependent enhancement (ADE) have not yet been described. Here, DenV infection enhanced the expression of inflammatory mediators and activation molecules in dendritic cells (DCs) through TLR2/MyD88 pathway. TLR2 appeared to facilitate DenV infection in DCs that were less permissive than macrophages for viral replication. In experiments using separate evaluations of DenV-infected and uninfected bystander DCs, infected DCs showed impaired maturation accompanied with TLR2-dependent production of inflammatory cytokines, by which uninfected bystander DCs showed increased expression of co-stimulatory molecules. Differential phosphorylation of MAPK and STAT3 was also detected between DenV-infected and uninfected DCs. Furthermore, DenV infection stimulated Th2-polarized humoral and cellular immunity against foreign and DenV Ag via TLR2/MyD88 pathway, and DenV-infected DCs were revealed to facilitate Th2-biased immune responses in TLR2-dependent manner. TLR2/MyD88-mediated Th2-biased Ab responses to primary DenV infection increased the infectivity of secondary homotypic or heterotypic DenV via ADE. Collectively, these results indicate that TLR2/MyD88 pathway in DC-priming receptors can drive Th2-biased immune responses during primary DenV infection, which could favor secondary DenV infection to DHF/DSS via ADE.