bluuebunny/crossref_metadata_2025_split huggingface dataset:
Tumor-associated myeloid cells convert indolent prostate cancer to aggressive disease
Authors: Sass Stephanie N , Gollnick Sandra O 
Published: January 2023

Abstract
Difficulties differentiating indolent from progressing prostate cancer (CaP) results in ineffective treatment strategies. Tumor-associated myeloid cells (TAMC) contribute to tumor progression; yet the role TAMC play in the conversion from indolent to progressing CaP is unclear. To test whether TAMC promote CaP progression we developed a murine model using two isogenic cell lines from the TRansgenic Adenocarcinoma of the Mouse Prostate (TRAMP) model. Tumorigenic C2 cells mimic progressing disease while non-tumorigenic C3 cells represent indolent disease. We report for the first time that CD11b+ TAMC isolated from C2 tumors co-injected with the non-tumorigenic C3 cells drive C3 tumor growth. In contrast, TAMC isolated from C2 tumor-bearing spleens or naïve spleens did not promote C3 tumor growth. This is the first indication that TAMC drive progression of indolent disease. Strikingly, tumor cells explanted from TAMC-induced C3 tumors were tumorigenic in the absence of additional TAMC, suggesting that TAMC induce stable changes within the C3 cells. These results have been recapitulated with the non-tumorigenic human cell line BPH-1 (benign prostatic hyperplasia). Furthermore, TAMC-induced tumor growth occurs via a TAMC secreted factor. Using a 5-day transwell system PC3M (human prostatic adenocarcinoma) TAMC were able to drive BPH-1 tumorigenesis. Future work will determine the factor secreted by TAMC and identify the molecular mechanisms responsible for tumor promotion. This work has the potential to identify critical factors responsible for the conversion of indolent to progressing disease thus laying the groundwork for novel prognostic and therapeutic strategies.
Elucidating the oncogene-driven regulatory T cell responses during melanoma tumorigenesis.
Authors: Chabanet Tamer Basel , Steinberg Shannon , Zhang Peisheng , Turk Mary Jo 
Published: January 2023

Abstract
Regulatory T cells (Tregs) are critical mediators of tumor immune suppression. While Tregs are found in established tumors, little is known about the kinetics and dynamics of Treg accumulation and the factors promoting it during oncogene-driven tumorigenesis. The present studies characterize Treg response kinetics and conversion dynamics during early tumor development in a model of autochthonous, tamoxifen-inducible BrafV600E Pten−/− melanoma. While microscopic skin dysplasia appeared 16 days following tumor induction, FoxP3+ Treg frequency and absolute numbers accumulated by day 26, coinciding with locally-invasive neoplasm development. BrafV600E inhibition with PLX4720 prevented Treg accumulation, suggesting that oncogenic Braf controls this process. Following adoptive transfer of CD4+ T cells specific to TRP-1, antigen-specific FoxP3+ Tregs preferentially accumulated in tumor-induced skin and draining lymph nodes (dLNs), as compared to tumor-free counterparts. In contrast, depleting Tregs prior to transfer abrogated the TRP-1-specific Treg response, suggesting a predominant role for natural Tregs. Furthermore, we observed an increase in chemokine (C-C motif) ligand 17 (Ccl17) and Ccl2 prior to Treg influx to tumor-induced skin. Oncogenic Braf regulated expression of Ccl17 and Ccl2, both of which mediated Treg migration in vitro. We are currently investigating the putative role of Ccl17/2-Ccr4 chemotactic axis in Treg recruitment to sites of Braf-driven tumorigenesis in vivo.
Reverse engineering B. Schlosseri developmental-regulated cell death programs for cancer immunotherapy
Authors: Corey Daniel M , Ring Aaron , Rosental Benyamin , McCracken Melissa , Weissman Irving L 
Published: January 2023

Abstract
B. schlosseri, a colonial marine species, offers a unique platform to study mechanisms underlying cellular recognition. We used adoptive transfer studies, FACs analysis, and RNA-sequencing to study the progression by which fused-colonies eliminate chimeric partners. We show the principle cell type mediating elimination of partners in a chimera is a cytotoxic Morula cell (MC), which utilizes developmental-regulated programmed cell death pathways, initiated during the ‘takeover’ phase of colony life, to eliminate partners. Adoptive transfer of FACs purified cytotoxic MCs from third party donors into recipients recapitulates events of chimeric partner elimination. Transfer of 1×10^5 allogeneic MCs eliminated 33 of 78 (42%) of recipient palleal buds and 20 of 76 (20.5%) adult zooids by day 14 post-transfer. Transfer of phagocytic populations had only minimal effects on recipient colonies. We identified 275 genes (FDR &lt; 0.05) from global RNA-seq expression profiling that increased by expression of at least 50 fold associated with elimination of chimeric partners. These include an IL-17 family member (IL-17C), the phagocytic receptors (MerTK, AXL), and programmed cell removal factors (CALR, MFGE-8). To probe the role of specific receptors we used in vitro studies. Recombinant Il-17c promoted allogeneic cytotoxicity while MFGE-8, a phosphatidylserine binding protein, induced engulfment of apoptotic cells. Studies using chimeric phosphatidylserine binding-cytokine fusion proteins are underway. Preliminary data suggests these fusion proteins promote inflammatory turnover of apoptotic cells. These studies provide new insights by which reverse engineering cell death programs can be utilized to enhance anti-tumor immunity.
Nanovaccine-based immuno-gene therapy: Targeting microRNA-148a for reprogramming tumor-associated dendritic cells in vivo
Authors: Ma Yifan , Liu Lanlan , Yi Huqiang 
Published: January 2023

Abstract
Immunosuppressive tumor-associated dendritic cells (TADCs) are a major obstacle for developing effective cancer vaccines. However, reprogramming TADCs in vivo remains to be difficult due to their poor responsiveness to TLR stimulation. Herein, we have identified a dysregulated miR-148a/DNMT1/ SOCS1 axis as a unique mechanism for dampened TLR3 stimulation in TADCs, in which tumor-elevated miR-148a increased immunosuppressor SOCS1 through targeting DNMT1, thereby abolishing TLR3-stimulated TADC maturation. However, targeting miR-148a with miR-148a inhibitor (miR-148ai) effectively recovered the sensitivity of TADCs to TLR3 stimulation through modulating the miR-148a/ DNMT1/SOCS1 axis. More importantly, the codelivery of miR-148ai and poly I:C (TLR3 agonist) with nanovaccines not only synergistically induced TADC maturation in vivo, but also ameliorated tumor immunosuppression, thereby leading to robust anti-cancer immunity and dramatic tumor suppression. This study proposes a nanovaccine-based immuno-gene therapy with the integration of miR-148a inhibition and TLR3 stimulation as a novel therapeutic approach to boost anti-cancer immunity by reprogramming TADCs in vivo.
microRNA-155 is a master regulator of dendritic cell function in breast cancer
Authors: Fan Daping , Wang Junfeng 
Published: January 2023

Abstract
In anti-tumor immunity, dendritic cells (DCs) capture, process and present tumor antigens to T cells, and initiate a tumoricidal response. However, DCs are often found dysfunctional due to their exposure to the tumor microenvironment (TME), leading to tumor escape from immune surveillance. The mechanisms underlying the regulation or dysregulation of DC function in the context of tumor has not been well elucidated. Here a vital role of microRNA-155 (miR-155) in regulating the function of DCs in breast cancer is reported. miR-155 expression is closely correlated with the maturation status, migration ability and cytokine production of DCs, as well as their ability to activate T cells. We further demonstrate that miR-155 regulates DC migration through epigenetic modulation of CCR7 expression. Moreover, IL-6 and IL-10, two cytokines abundant in the TME, are found to impair DC maturation by suppressing miR-155 expression. Animal studies show that lack of miR-155 diminishes, while forced expression of miR-155 enhances, the effectiveness of DC-based immunotherapy for breast cancer. These findings suggest miR-155 is a master regulator of DC function in breast cancer, and boosting the expression of a single microRNA, miR-155, may significantly improve the efficacy of DC-based immunotherapies for breast cancer.
NKT ligand loaded E6/E7 Antigen expressing B cell & Monocyte based Vaccine effectively controls growth of heterogeneous tumors containing MHC Class I deficient cells by reversal of NK cell anergy
Authors: SEO HYUNGSEOK , JEON IN-SU , Kang Chang-Yuil 
Published: January 2023

Abstract
MHC Class I downregulation or deficiency has been reported in advanced tumor microenvironments of clinical cases. Malignant transformation and in vivo selection of highly metastatic cells show MHC Class I loss neoplasm, which contributes to the evasion of tumor from the host immune system. These tumor microenvironments are major impediments for cancer immunotherapy, thereby imposing restriction of cytotoxic T lymphocytes. Besides, it has been reported MHC Class I low states induce NK cell anergy, which interrupt NK cell mediated antitumor immune responses. To overcome these limitations, we designed NKT ligand loaded, E6/E7 Ag expressing b cell & monocyte based vaccine. We found our vaccine elicited NKT, NK cell and Ag specific CTL response, and effectively eradicated solid tumors. We also found a negative correlation between tumor growth and MHC Class I expression level. When the MHC Class I expression level was lowered, the major antitumor effector cell is changed from CTL to NK cells. Thus, we generated a MHC Class I knock out tumor cell line for testing our vaccine effects on MHC Class I deficient situation to mimic actual clinical cases. We established heterogeneous tumor models, which contains various percent of MHC Class I KO tumor cells. The data show our vaccine eliminated heterogeneous tumors, which contains up to 10% MHC Class I KO cells, and effectively eradicated of MHC Class I KO cells via NKT, NK cell. Moreover, our data show this NK anergy in MHC class I KO tumor-bearing mice was reversed by our vaccination via NKT cell producing cytokines. Taken together, our vaccine induced diverse immune responses overcoming immunoresistant tumor microenvironment and is expected to effectively cure advanced tumor patients in clinical trials.
Combination of IL-12 and radiotherapy induced regression of large orthotopic liver cancers through modulation of immune cells in tumor microenvironment
Authors: Wu Chia-Jen , Tsai Yi-Ting , Lee I-Jung , Wu Ping-Yi , Tao Mi-Hua 
Published: January 2023

Abstract
Hepatocellular carcinoma (HCC) is one of the leading causes of cancer death worldwide with few therapeutic options. Radiation is wildly used for cancer treatment, but local relapse often occurs. Interleukin 12 (IL-12) has potent antitumor activities by activating natural killer cells (NK) and CD8+ T cells, reprogramming myeloid cells to an immune active phenotype, and inhibiting new blood vessel formation. We hypothesized that combined radiation and IL-12 treatment may change tumor suppressive microenvironment and induce antitumor immune responses. Our data showed that only combination of radiation and intratumoral injection of adenovirus encoding IL-12 (Ad/IL-12) led to tumor regression in mice with large subcutaneous or orthotopic HCC, and significantly prolonged their survival. Mechanistic studies revealed that combination therapy enhanced antigen (Ag) presentation ability of DCs by increasing MHC class II, CD40 and CD86 expression. Combination therapy also significantly reduced numbers of tumor-infiltrating myeloid-derived suppressor cells (MDSCs) and impaired their suppressive functions by reducing reactive oxygen species (ROS) production. Accordingly, combination therapy significantly increased the cell numbers of tumor-infiltrating CD8+ T cells and their expressions of CD107a and TNF-α. The cell numbers of tumor-infiltrating NK cells was not affected, but the expression of activation markers was significantly increased after treatment. Together, our results demonstrate that combination therapy effectively against advanced HCC through activating tumor-infiltrating NK cells and tumor-specific CD8+ T cells, enhancing Ag presentation ability of DCs while reducing the suppressive functions of MDSCs.
NK cells are not lytic and act exclusively as helper cells in the gp96-mediated immune response
Authors: Sedlacek Abigail L , Kinner Lauren B , Binder Robert J 
Published: January 2023

Abstract
Through release from necrotic cells or extraneous administration, immunogenic Heat Shock Proteins (HSPs) in the extracellular environment elicit T cell responses with specificity to the peptides that the HSPs chaperone. Hence, immunogenic HSPs carry the antigenic fingerprint of the cell from which they are isolated. Thus, tumor derived gp96 (a prototypical immunogenic HSP) is being investigated as a potential immunotherapy. CD4+ and CD8+ T cell responses are elicited following immunization with gp96 and are dependent on a cross-priming antigen presenting cell (APC). While a role for natural killer (NK) cells has been postulated, their function in the gp96-mediated immune response is unknown. In these studies, we investigated how NK cells are activated following immunization with gp96 and what role they play in the ensuing immune response. We show that NK cells are indirectly activated by gp96 matured APCs. Following immunization with tumor-derived gp96, we show that while NK cells are essential during the effector phase of the anti-tumor immune response in vivo, they do not exhibit increased target cell lysis ex vivo. Alternatively, they produce IFNγ and are necessary for T cell mediated target lysis and optimal APC maturation. We’ve compared gp96 activated NK cells to those indirectly activated by other mediators (LPS and IL-2) and determined that gp96 activated NK cells present a unique phenotype where IFNγ production is observed, but other classical functions associated with activated NK cells, i.e. increased expression of granzyme B, do not occur. Collectively, these data indicate that gp96-activated NK cells act exclusively as helper cells to mediate the anti-tumor immune response.
Improving the immunogenicity of dendritic cell-derived exosome-based vaccines for the immunotherapy of melanoma
Authors: Damo Martina , Wilson D. Scott , Simeoni Eleonora , Hubbell Jeffrey A. 
Published: January 2023

Abstract
Dendritic cell (DC)-derived exosomes (Dexo) are promising vaccine candidates for the treatment of cancer.
We aimed at identifying a Dexo formulation with stronger immune stimulatory properties and efficacy as compared to the Dexo vaccines previously tested in pre-clinical and clinical settings of cancer immunotherapy. We therefore produced Dexo from DCs loaded with specific antigens and matured with the Toll-like receptor (TLR)-3 ligand poly(I:C) as danger signal.
In vivo, Dexo produced from DCs loaded with OVA and stimulated with poly(I:C) could induce efficient activation of endogenous OVA-specific CD4+ and CD8+ T cells, leading to pro-inflammatory Th1 immune responses.
We subsequently produced Dexo from DCs matured with poly(I:C) and cultured in the presence of oxidized B16F10 cell lysates (Dexo(B16+pIC)) as a source of B16F10 antigens.
Mice bearing subcutaneous B16F10 tumors were vaccinated intradermally to target tumor-draining lymph nodes (tdLN), resulting in reduced tumor growth, limited metastasis burden and, most importantly, in prolonged survival of the mice vaccinated with Dexo(B16+pIC). Such benefits were associated with increased frequencies of effector CD8+ T cells in the tdLNs, spleen and tumor masses, reduced frequencies of tumor-infiltrating exhausted PD-1+ CD8+ T cells and increased frequencies of tumor-infiltrating NK and NK-T cells obtained upon vaccination with Dexo(B16+pIC) as compared to Dexo(B16), which instead are devoid of poly(I:C) and resemble the Dexo vaccines previously tested in human patients.
Our results demonstrate that poly(I:C) is a promising candidate for the production of Dexo vaccines with improved immune stimulatory properties suitable for the immunotherapy of cancer.
Naturally-derived bacterial nano-particles engage diverse innate receptors, driving the activation of dendritic cells and leading to the establishment of potent adaptive immune responses.
Authors: Davitt Christopher JH , Petersen Hailey E , Kikendall Nicole L , Lavelle Edward C , Morici Lisa A 
Published: January 2023

Abstract
Most non-living vaccines in clinical use are thought to mediate protection primarily via antibody responses; however, many intracellular bacterial infections require cell-mediated immunity (CMI) for protection. This renders traditional strategies insufficient and drives a need for new approaches to elicit CMI. Outer-membrane vesicles (OMVs) derived from Gram-negative bacteria are an effective vaccine platform with precedence for safe use in humans. Unlike most subunit antigens and synthetic nano-particles, OMVs contain endogenous immunostimulatory ligands and deliver antigens in their native orientation. We hypothesized that OMVs could activate antigen presenting cells through the engagement of various innate receptors and drive CMI through the three key activation steps: antigen-presentation, co-stimulation and cytokine production. Following OMV uptake in vitro and in vivo, dendritic cells (DCs) increased surface MHC class I and II (MHCcII), CD80, and CD86 expression. OMV-stimulated DCs produced significantly more of the key T cell polarizing cytokines IL-1β, IL-6, IL-18 and IL-12p70 compared to DCs treated with heat-killed (HK) bacteria. TLR-4 contributed to OMV-mediated expression of MHCcII, CD80, and IL-1β, IL-6, IL-18 and IL-12p70, while the NLRP3 inflammasome was required for OMV-induced production of IL-1β and IL-18. Following vaccination of mice, Th1- and Th17-type T cell responses were observed after ex vivo restimulation with OMVs and HK bacteria. In addition, OMV vaccination produced functional CD8+ T cells capable of killing bacteria-infected cells. Collectively these results support the utility of the OMV platform as a non-living vaccine that can lead to protective CMI against bacterial pathogens.
Collection and characterization of potentially novel antimicrobial peptides from Japanese medaka plasma
Authors: Dong Miao , Lei Haipeng , Humble Joseph L , Liang Yimin , Shen Wei , Au Doris W.T. , Sun Hongyan , Lam Yun Wah 
Published: January 2023

Abstract
The excessive use of antibiotics in aquaculture contributes to the uprising of antibiotic resistance that threatens human health. We explore the innate immunity of fish for naturally occurring antimicrobial factors that can be developed into potential antibiotic agents. Antimicrobial peptides (AMPs) have been studied in many organisms but efforts on the systematic identification of AMPs in fish have been lacking. In this study, we systematically identified naturally occurring peptides in medaka plasma. Blood collected from medaka of different gender, age and infection status were combined. Peptides under the molecular weight of 3kDa were fractionated and purified, followed by mass spectrometry analysis. In total, 6483 unique peptides were identified against the medaka genome, constituting a database of circulating peptides in this organism. After evaluation with a combination of web-based prediction tool and conserved physicochemical properties of AMPs, 83 potential antimicrobial peptides were predicted. One of them, a 13-residue peptide named VPS13D3241–3253, showed a broad-spectrum toxicity on fish and human pathogenic bacteria (gram+ or gram−) without significant cytotoxicity on mammalian cell lines. Scanning electron microscopy indicated that VPS13D3241–3253 disrupted the cell wall of both gram+ and gram− bacteria. SOS response assay showed that this peptide efficiently induced DNA damage in bacteria. The identification of VPS13D3241–3253 illustrates the feasibility of the proteomic approach in the discovery of potentially novel AMPs from fish. These AMPs will form an important basis for the development of new antibacterial agents in the fish farming industries.
Sterilizing immunity to influenza virus infection requires local antigen-specific T cell response in the lungs
Authors: Dutta Avijit , Huang Ching-Tai , Chen Tse-Ching , Lin Chun-Yen , Lin Yung-Chang , Chang Chia-Shiang , He Yueh-Chia , Huang Yu-Lin 
Published: January 2023

Abstract
Pre-infection induces sterilizing immunity to homologous influenza virus challenge in ferret. In our antigen-specific experimental system, mice pre-infected with PR8 influenza virus through nasal route are likewise resistant to reinfection of the same strain of virus. The virus is cleared before establishment of effective infection. Intramuscular influenza virus injection confers protection against re-infection with facilitated virus clearance but not sterilizing immunity. Pre-infection and intramuscular injection generates comparable innate immunity and antibody response, but only pre-infection induces virus receptor reduction and antigen-specific T cell response in the lung. Pre-infection with nH1N1 influenza virus induces virus receptor reduction but not PR8 specific T cell immune response in the lung and cannot prevent infection with PR8 influenza virus. Pre-infection with PR8 virus induced PR8-specific T cell response in the lung but cannot prevent infection with nH1N1 virus either. Antigen specific T cell immunity is required for sterilizing immunity. We discuss the potential implications of these findings in vaccination strategy for effectual protection comparable to pre-infection.
Antigen presenting cell subsets in the lung and draining lymph nodes affect granzyme B-expressing CD4+ T cells in the lung during influenza A infection
Authors: Price Jeffrey D. , Brown Deborah M. 
Published: January 2023

Abstract
Influenza A virus (IAV) is a global health burden that evades vaccine responses and can present as a pandemic threat. Innate immune cells are the first line of defense at the mucosal site of entry and drive adaptive responses that provide immunity. Therefore, we examined the distinct antigen-presenting cell (APC) populations in the lung and draining lymph nodes that respond to IAV infection. When mice are treated intranasally with PR8, a highly inflammatory H1N1 IAV, the populations of APCs in the lung change, inducing infiltration of a large population of inflammatory macrophages and a concomitant decrease in dendritic cells. These inflammatory macrophages express increased levels of TLR9 after infection, corresponding with our previous work demonstrating the efficacy of CpG DNA in driving anti-IAV responses. These changes in APC subsets do not occur in a similar fashion after infection with X31, a low inflammation H3N2 virus, or in the lymph nodes. One significant response is the production of granzyme B (GzB) in CD4+ T cells that infiltrate the lung after IAV infection. APC populations were sorted after PR8 infection and used to stimulate DO11.10 T cells in vitro. CD11b+ APCs were most efficient at inducing GzB in CD4+ T cells in steady-state, while after infection both CD11b+ and CD11b+CD11c+ APCs induced strong GzB expression, while all APC subsets induced IL-2 and IFN-gamma release from CD4+ T cells. These results have implications for vaccine design and we are currently utilizing chimeric antibodies to target antigen to APC populations in the lung and lymph nodes to induce anti-IAV CD4+ T cell responses.