bluuebunny/crossref_metadata_2025_split huggingface dataset:
Expression of IFNgR on tumor cells impact response to anti-CTLA-4 (TUM2P.1034)
Authors: Gao Jianjun , Shi Lewis , Xiong Liangwen , He Qiuming , Chen Jianfeng , Shen De-Yu , Sharma Padmanee 
Published: January 2023

Abstract
Blockade of T cell co-inhibitory receptor CTLA-4 with a monoclonal antibody, Ipilimumab (BMS), has led to augmented anti-tumor immune responses, clinical benefit, and FDA approval of Ipilimumab for the treatment of metastatic melanoma. Our published data indicate that anti-CTLA-4 treatment resulted in marked increase of IFN-gamma (IFNg) production by CD4 T cells expressing inducible costimulator (ICOS). Studies in mice have demonstrated the importance of IFNg for effective anti-tumor responses. We hypothesized that tumor cell expression of IFNg-receptor (IFNg-R) would be necessary for tumor regression mediated by anti-CTLA-4. To test our hypothesis, we conducted both in vitro and in vivo experiments with tumor cell lines containing knockdown of IFNg-R. In the presence of IFNg, proliferation of tumor cells was inhibited; however, tumor cells lacking IFNgR were resistant to IFNg and were able to proliferate. In addition, mice inoculated with tumor cells lacking IFNgR were treated with anti-CTLA-4 and found to have impaired tumor rejection and higher mortality as compared to mice bearing tumor cells with intact IFNgR. Our data strongly suggest that intact IFNg-R expression and signaling on tumor cells is important for anti-CTLA-4-mediated anti-tumor responses. Our data point to a potential mechanistic pathway to explain why some patients may respond to therapy while others do not and we’re evaluating tumor samples from patients treated with anti-CTLA-4 to test this concept.
Identification of miRNA-338-5P as an effector of the tumor suppressor activity of immunized anticancer bioactive peptide-3 (TUM2P.1036)
Authors: Su Xiulan , Zhang Jialing , Yu Lan , Xing Zhiwei , Liang Junqing , A Nanda 
Published: January 2023

Abstract
Gastric cancer remains one of the leading causes of global cancer mortality. Cancer stem cells (CSC) have been studied in many solid tumors, including gastric cancer and they are promising for the development of anticancer drugs that can target all CSC subsets within a tumor to prevent recurrence. Previously, we identified a novel anti-cancer bioactive peptide (ACBP), which isolated and purified from goat liver following immunization with human gastric cancer protein extract, and designated as ACBP-3. ACBP-3 inhibited cell proliferation and clone formation of gastric cancer stem cells (CSCs). In present study, we investigated the mechanism of ACBP-3 inhibition of gastric CSCs in vitro and in vivo. We employed a microRNA array and screened for the genes of which had increased expression by ACBP-3 in CD44 positive gastric carcinoma cell lines MKN45 and MKN74. MiRNA-338-5p showed the greatest difference in the expression level. In vivo, ACBP-3 alone significantly inhibited MKN45 tumor growth in a xenograft nude mouse model. The tumor tissues were harvested after treatment, and ACBP-3 treatment induced expression of miRNA-338-5p, Bac, and Bim as quantified by RT-PCR and western blot. Overexpression of miRNA-338-5p reduced cell proliferation and induced apoptosis in both MKN45 and MKN74 cell lines in vitro. We concluded that miRNA-338-5p is the effector of tumor suppressor activity of ACBP-3 in gastric cancer stem cells. ACBP-3 could be a potential anti-cancer agent.
Mantle cell lymphoma associated sphingosine-1 phosphate inhibits natural killer T cell mediated antitumor responses (TUM2P.1042)
Authors: Webb Tonya , Kimball Amy , Sun Wenji 
Published: January 2023

Abstract
The incidence of lymphoma in the US is rising. While chemoimmunotherapy causes remissions in mantle cell lymphoma (MCL), responses are not durable and most patients relapse. New strategies that focus on eliminating tumor-associated immunosuppressive factors are needed to improve patient outcomes. One of the earliest pathways to be activated during an immune response is CD1d-mediated presentation of lipid antigens to natural killer T (NKT) cells. We have found that MCL patients have a significant reduction in circulating NKT cell number and function. We hypothesized that MCL-associated sphingosine-1 phosphate (S1P) can down regulate CD1d-dependent NKT cell responses to MCL. We found that inhibition of S1P signaling in MCL cell lines led to increased CD1d-mediated NKT cell activation, as assessed by cytokine production and cytotoxicity. Furthermore, knockdown of sphingosine kinase 1 in MCL cell lines resulted in the presentation of an activating endogenous antigen. These results demonstrate that S1P regulates CD1d-mediated antigen processing and presentation to NKT cells by altering the endogenous repertoire of lipid antigens and suggest that targeting this pathway could be an important immunotherapeutic strategy.
Novel RORgamma agonists enhance anti-tumor activity of adoptive T cell therapy (TUM2P.1010)
Authors: Carter Laura , Moisan Jacques , Majchrzak Kinga , Hu Xia , Morgan Rodney , Liu Xikui , Demock Kellie , Wang Yahong , Lesch Chuck , Sanchez Brian , Bousley Dick , Taylor Clarke , Van Huis Chad , Skalitzky Don , Aicher Tom , Toogood Peter , Zou Weiping , Paulos Chrystal , Glick Gary 
Published: January 2023

Abstract
Adoptive cell transfer (ACT) therapy using tumor infiltrating lymphocytes (TILs) or T cells modified to express chimeric antigen receptors is a promising anti-cancer approach. Evidence suggests that Th17 or Tc17 cells display superior anti-tumor activity over unpolarized T cells commonly used in ACT clinical trials. As an approach to improve the potency and persistence of ACT, synthetic RORɣ agonists were designed to bolster the generation of type 17 cells. In vitro stimulation in the presence of RORɣ agonists modulates expression of costimulatory and coinhibitory molecules and increases IL-17A, IL-22 and GM-CSF production while maintaining IFNɣ production. Additional investigation revealed that treating tumor-specific Th0, Th17, Tc0 or Tc17 T cells with a RORɣt agonist in vitro significantly enhanced their ability to regress large and established EG.7 lymphoma and B16F10 melanoma tumors in vivo. Animals receiving RORɣ agonist-treated T cells had increased frequency of transferred cells, elevated IL-17A levels and decreased PD-1 expression in tumors and spleen compared to control animals. Previous studies have also shown that systemic delivery of an RORɣ agonist can also enhance anti-tumor immune response in syngeneic pre-clinical tumor models. By enhancing cytokine/chemokine production, promoting survival as well as decreasing PD-1 expression, RORɣ agonist molecules provide an effective means to enhance the potency of adoptively transferred T cell products.
Combination immunotherapy utilizing influenza infection and PD-1 blockade reduces lung melanoma tumor growth (TUM2P.1011)
Authors: Zloza Andrew , Broucek Joseph , Redondo Raquel , Zayas Janet , Lusciks Jevgenijs , Dolubizno Hubert , Grin Alisa , Kohlhapp Frederick , Kaufman Howard 
Published: January 2023

Abstract
Emerging epidemiological studies report increased cancer occurrence in patients with chronic viral infections, even when such infections are non-oncogenic and not in the same tissue as the cancer. In our recent studies, we observed decreased anti-tumor immune responses in the context of concomitant infection. Specifically, we discovered that anti-melanoma (gp100) CD8+ T cell responses in mice challenged with melanoma are shunted from the tumor site (skin) to the site of influenza infection (lung), leading to faster tumor growth and hastened host death. We observed similar findings with multiple tumor and virus combinations, including patient-derived melanomas in humanized mice infected with HIV. Based on this infection-mediated shunting of anti-tumor CD8+ T cells to the infection site, and towards developing related therapeutic interventions, we sought to determine whether an infection in a particular tissue would improve anti-tumor responses against a tumor also in that same tissue. We discovered that influenza infection within the lungs resulted in 51% fewer tumor foci within the lungs compared to no infection. Tumor foci were further reduced with systemic PD-1 blockade (more than 70% fewer tumor foci compared to no infection or PD-1 blockade alone). Future studies will further dissect the mechanisms underlying these findings in the setting of viral infection. We ultimately aim to translate these findings to combination cancer immunotherapies utilizing viral infections.
Interleukin-7 receptor contributes to increase of wound-healing migration as well as Invasion in the prostate cancer (TUM3P.1049)
Authors: Seol Min , Kim Jin-Hee , Oh Keunhee , Sim Ji Hyun , Lee Sun-Kyung , Shin Young-Kyoung , Kim Woo-jong , Lee Dong-Sup , Han Ilkyu , Ku Ja-Lok , Kim Hang-Rae 
Published: January 2023

Abstract
IL-7Rα plays a critical role in the development and maintenance of immune cells but no studies suggest a verification of a key factor of bone metastasis. To investigate the role of IL-7Rα on bone metastases from prostate cancer, we evaluate the expression of IL-7Rα, wound healing migration, invasion, and zymography on the prostate cancer cells after IL-7 treatment. As results, the expression of IL-7Rα in PC-3 cells was higher than in other metastatic cell lines. Not only wound-healing but also invasion was increased after IL-7 treatment at the PC-3 cells. And, MMP2, MMP9 was also increased in PC-3 cells upon IL-7 stimulation. Moreover, the invasiveness of cells overexpressing IL-7Rα (PC-3IL-7Rα OE) was significantly increased compared to control cells. Furthermore, in order to elucidate the role of IL-7Rα in bone metastasis, PC-3IL-7Rα OE cells were administered into NSG mouse by intra-cardiac injection. Metastasis into the bone was markedly increased when PC-3IL-7Rα OE were injected compared with control vector expressed PC-3 cells. In conclusion, migration and invasion were increase in PC-3 cells after IL-7 treatment. Metastasis into bone was enhanced by PC-3IL-7Rα OE, suggesting IL-7Rα might be involved in migration as well as invasion in the bone metastatic prostate cancer. Acknowledgement: This research was supported by National Research Foundation of Korea (2014M3A7B4052194 for H Kim and 2014R1A6A3A01058743 for J Kim)
Potential signaling molecules involved in the progression of metastatic prostate, breast and colorectal cancer (TUM3P.1051)
Authors: Ejaeidi Ahmed , Cruse Julius , Lewis Robert , Craft Barbara , Puniky Louis 
Published: January 2023

Abstract
Metastases and their complications lead to death in up to 90% of cancer patients. Hematogenous metastasis is associated with loss of cell adhesion, migration in the blood (as individual circulating tumor cells, (CTC) or clusters), adhesion to the target organ and proliferation to form metastases. The present investigation was designed to demonstrate key molecules in the sera of metastatic cancer patients that induce ERK 1/2 and Survivin protein expression. We showed that CTCs grown in media supplemented with patient sera express the potential to form colonies and spheres followed by senescence. The cultured CTCs overexpressed ERK and Survivin, which reflects their aggressiveness. We demonstrated by immunofluorescence and western blot, with confirmation by qRT-PCR (in progress), that prostate, breast and colorectal cancer-derived cell lines cultured in media supplemented with sera from patients with CTCs, induced expression of ERK 1/2 and Survivin proteins. Using the MTT assay, we demonstrated that cancer-derived cell lines treated with sera from CTC positive patients showed accelerated proliferation compared to controls. It is anticipated that correlation with clinical data might reveal future potential targets for adjuvant therapy to minimize the risk of metastasis.
Identification and characterization of novel immunosensitizing therapeutics for melanoma (VAC3P.1060)
Authors: Tsai Alexander , Davila Eduardo 
Published: January 2023

Abstract
Recent breakthroughs in the field of immunotherapy have revolutionized the treatment of melanoma patients. Specifically, immune checkpoint blockade of CTLA-4 and PD-1 have prolonged overall survival in a subset of melanoma patients. Despite dramatic and durable results in some cases, low overall response rates to these therapies leave the majority of melanoma patients without effective immunotherapeutic treatment options. In order to identify immunotherapies which might offer improved response rates with the potential to be rapidly translated to the clinic, we developed a high-throughput screen and tested over 2000 compounds, many of which are FDA-approved for various malignancies or other diseases. The screen revealed distinct families of multikinase inhibitors and DNA-damage repair inhibitors as novel melanoma immunosensitizing agents. We show that these two classes of drugs can reduce the expression of various immunosuppressive molecules (e.g. PD-L1, CD155) on the cell surface of a wide variety of genetically distinct human melanoma cell lines. Notably, the drugs also increased the expression of HLA and melanoma antigens in most cases. Importantly, preliminary data suggests that drug treatment sensitizes melanoma cells to T cell mediated cytotoxicity. Further preclinical studies are underway to verify drug targets, identify mechanisms of action, and establish in vivo anti-tumor activity.
Immune mechanisms associated with enhanced influenza A virus disease versus cross-protection in vaccinated pigs. (VAC4P.1064)
Authors: Hughes Holly , Olson Zahra , Gauger Phillip , Vincent Amy , Brockmeier Susan , Loving Crystal 
Published: January 2023

Abstract
Vaccine associated enhanced respiratory disease (VAERD) has been described in pigs vaccinated with whole-inactivated influenza virus (WIV) following infection with heterologous influenza A virus (IAV). WIV vaccination elicits production of cross-reactive, non-neutralizing antibody to the challenge IAV strain suggesting circulating immune complexes and/or antibody dependent cell-mediated cytotoxicity could contribute to pathology. Moreover, pathological findings in VAERD lungs include significant lymphocytic infiltration and increased levels of proinflammatory cytokines. In order to further delineate the immune mechanism associated with VAERD versus partial-protection we defined the lymphocyte populations infiltrating the lungs following challenge, as well as level of complement activation. Post-challenge, IAV-specific IFNγ secreting cells in the lungs were increased in pigs with VAERD compared to non-vaccinated, challenged controls. CD8 T cells and NK cells were significantly higher in the lungs of pigs protected from homologous challenge, suggesting these cells may play a role in protection. Interestingly, pigs with VAERD had a significant increase in memory T cells that was not observed in pigs without VAERD. Additionally, complement activation was significantly higher in the lungs of pigs experiencing VAERD. These data further describe the lymphocytic pathology associated with VAERD and suggest a role for complement activation in the development of VAERD disease pathology.
Autoimmunity-predisposing PTPN22 C1858T variant associates with diminished human CD4 T cell responses to seasonal influenza vaccination (VAC4P.1112)
Authors: Crabtree Juliet , Tien Shelly , Ferment Valerie , Guan Weihua , Peterson Erik 
Published: January 2023

Abstract
PRR-induced Type I IFN is necessary for optimal host responses to antiviral immunization, including CD4 T cell expansion and neutralizing antibody production. The magnitude of T and B cell vaccine responses correlates with protection against influenza virus infection. PTPN22 promotes TI IFN production after PRR engagement on myeloid cells. The autoimmune disease-associated C1858T variant of PTPN22 encodes an R620W substitution (PTPN22-W), which is a reduced function variant for TI IFN production. Since PTPN22-W carriers show reduced capacity for PRR-driven TI IFN production, we tested the hypothesis that PTPN22-W carriers will have diminished immune response to the influenza vaccine. Healthy PTPN22-W carriers (n=18) and age-matched controls were immunized with the 2013-2014 trivalent inactivated influenza vaccine, and immune responses were assessed. Carriers exhibited significantly decreased induction of influenza-specific CD4 T cells expressing TNFα, IL-2, and IFNγ at 2 weeks after immunization. Moreover, carriers show a trend toward impaired induction of neut. antibody titers post vaccination. We did not observe differences between carriers and controls between selected markers of the early interferon transcriptional response, possibly because of inadequate power to detect a partial phenotype. Nevertheless, defects in T cell immunity strongly suggest that PTPN22-W carriage predisposes to defective capacity for mounting protective immune responses to influenza vaccination.
Recombinant outer membrane protein: a potential candidate for Th17 based vaccine against Klebsiella pneumonia (VAC4P.1066)
Authors: Chen Kong , Kolls Jay 
Published: January 2023

Abstract
Bacterial pneumonia is a leading cause of mortality and one major pathogen associated with this disease is Klebsiella pneumoniae (KP). Recently, the emergence of antibiotic resistant strains demands an effective vaccine against these bacteria. We have previously shown that intranasal immunization with heat-killed KP or crude outer membrane proteins (OMPs) isolated from KP induced antigen specific Th17 responses and these Th17 cells conferred serotype independent protection against various clinical isolates of K. pneumoniae including the recently described multidrug resistant New Delhi Metallo-beta-lactamase-1 strain. To develop a clinically relevant vaccine, we cloned individual OMPs from K. pneumoniae and successfully expressed OmpX in the BL21 E. coli. The purified recombinant OmpX was recognized by KP immune serum by direct ELISA and also recognized by Th17 cells from KP immunized mice. In vivo, intranasal immunization of the purified OmpX induced robust mucosal Th17 responses and left IL-17 producing gamma-delta T cells unaffected. In combination with a mucosal adjuvant, both intranasal and intramuscular immunization provided serotype independent protection against live bacterial challenge. Taken together, these data demonstrated that OMPs serves as an excellent candidate for the development of clinical relevant vaccines against K. penumoniae especially the newly emerged antibiotic-resistant strains that impose great threat to the public health.
Improving immunity against mycobacteria by targeting iNKT cells in a partially humanized mouse model (VAC4P.1103)
Authors: Carreno Leandro , Batista-Gonzalez Ana , Prados-Rosales Rafael , Sharma Kharkwal Shalu , Yuan Weiming , Porcelli Steven 
Published: January 2023

Abstract
Invariant Natural Killer T cells (iNKT cells) are a specialized group of T lymphocytes which modulate many aspects of immune responses. They co-express an invariant T cell receptor (TCR) which recognizes glycolipid antigens bound to the CD1d molecule. Although mouse and human CD1d are relatively conserved, there are differences in the abundance and responses of human and mouse iNKT cells, which may correlate with differences in CD1d function. Thus, the study of iNKT cell responses and their role in disease models requires a more “humanized” model to enable more accurate translation of results to human therapy. Here, by using a human CD1d knock-in mouse, which displays similar frequency and phenotype in their iNKT cells to humans, we have vaccinated with different strains of potential tuberculos (TB) vaccine candidates carrying different glycolipid iNKT cell ligands. Our results shown that hCD1d-KI iNKT cells are able to enhance TB-specific T cell responses. We have also identified novel glycolipds with an enhanced ability to induce multifunctional T cells. Our results suggest that human CD1d knock-in mice are a valuable tool to study iNKT cell-based therapies.
CD20 peptides elicit a protective anti-tumor immune response in vivo (VAC5P.1126)
Authors: TEILLAUD JEAN-LUC , Riller Quentin , Siberil Sophie 
Published: January 2023

Abstract
We have investigated whether human CD20 (huCD20)-derived peptides are able to elicit a protective anti-tumor immune response in vivo. Based on in silico prediction and in vitro binding to recombinant MHC molecules (Kb, Db, and I-Ab), we first defined candidate peptides able to bind to various MHC molecules in a restricted manner (8-mers restricted to Kb, 9-mers restricted to Db, 15-mers and 20-mers restricted to I-Ab). Naive C57Bl/6 mice were then immunized s.c. with 7 different mixtures of these peptides in presence of adjuvants (CFA/IFA, Montanide ISA 51VG, CpG) and subsequently challenged with EL4-huCD20 tumor cells. Interestingly, a longer survival could be achieved in mice immunized with 5 of the 7 huCD20-derived peptide mixtures. In addition, MHC-peptide fluorescent pentamers (generated using peptides with the highest capacity of binding to MHC molecules) allowed the detection of anti-CD20 specific CD8+ T cells in one of the groups of immunized mice. Overall, we conclude that it is possible to define huCD20-derived peptides that elicit a T-cell response against EL4-huCD20 tumor cells. We suggest that these peptides could be the targets of the adaptive anti-tumor T cell response triggered by anti-CD20 treatment that we previously reported using a mouse model in which immune competent C57Bl/6 mice were i.v. injected with human CD20+ tumor cells and then treated with an anti-huCD20 mAb (1,2). 1. Abès et al., Blood, 2010 2. Deligne et al., Leukemia, 2014
Safety and immunogenicity of the Ad35/AERAS-402 tuberculosis vaccine in a phase 2 dose-finding clinical trial in BCG-vaccinated healthy infants (VAC5P.1119)
Authors: Hokey David , Tameris Michele , Henson Dawn , Dheenadhayalan Veerabadran , Blatner Gretta , McClain Bruce , Walker Robert , Hatherill Mark , Nduba Videlis , Sacarlal Jahit , Gray Glenda , Hendriks Jenny , Pau Maria , Douoguih Macaya , Sadoff Jerald , Barker Lewellys 
Published: January 2023

Abstract
Despite widespread use of BCG, tuberculosis (TB) remains a global threat, with 9 million new cases and 1.5 million deaths reported in 2013. Current vaccine candidates in clinical trials are designed to replace BCG or boost the variable efficacy observed with BCG. One of these is AERAS-402, a replication-deficient Ad35 vaccine encoding a fusion protein of the M. tuberculosis antigens 85A, 85B, and TB10.4. This vaccine has been tested in adults, infants, HIV+ adults and patients on or following treatment for TB and shown to be safe and immunogenic. A phase 2 clinical trial of two doses of AERAS-402 was conducted in healthy infants in South Africa, Kenya, and Mozambique. The original study design consisted of a dose-finding phase followed by an efficacy phase at the selected dose. The trial design was modified to include a third dose of AERAS-402. AERAS-402 was well-tolerated at all dose levels and up to three doses. Despite the addition of a third dose, the predefined immunogenicity target was not met and the efficacy portion of the trial was removed. The third dose failed to increase immune responses, which consisted of a dominant polyfunctional (IFN-γ, IL-2, TNF) and bifunctional (IFN-γ, TNF) CD8 response and a lower magnitude polyfunctional and bifunctional (IL-2, TNF) CD4 responses. These responses were considerably lower than those observed in adults. Alternative methods to enhance responses to AERAS-402, such as heterologous prime-boost approaches, are warranted.