Medical Immunology Commons^™

Combinatorial Immunotherapy Drives Exhaustion In Tumor Antigen–Specific Cd8+ T Cells Within The Mouse Renal Tumor Microenvironment, Holly R. Stephens, Elizabeth Elkins, Jing Li, Zoey N. Swalley, Henry Nnaemeka Ogbonna, Pia Muri, Zachary Roberts, Francesca R. Dempsey, Md Akkas Ali, Md Hasanul Banna Siam, Richard Kirkman, Jianqing Zhang, Sunil Sudarshan, Daniel J. Tyrrell, Hubert M. Tse, Daniel L. Smith Jr, Lyse A. Norian

Microbiology, Immunology, and Molecular Genetics Faculty Publications

Immunotherapies have greatly improved outcomes for patients with renal cell carcinoma (RCC), yet response rates remain suboptimal and the factors promoting therapy resistance versus sensitivity are incompletely understood. Currently, no preclinical model of orthotopic renal cancer exists that permits evaluation of tumor antigen–specific (TAS) CD8⁺ tumor-infiltrating lymphocytes (TILs). To address this deficiency, we developed a mouse renal cancer model that permits tracking of adoptively transferred TAS CD8⁺ T cells. Renca-LUC tumor cells were transduced to express tumor ERK (tERK), a model antigen expressing a one-amino-acid change from wild-type ERK, resulting in recognition by tERK/H-2K^d-specific DUC Thy1.1 …

Immunopathogenic Crosstalk Between Cancer And The Kidney: A Central Role For Macrophages As Potential Mediators., Dana Hammouri

Electronic Theses and Dissertations

Cisplatin remains a mainstay in the treatment of solid tumors, yet its therapeutic efficacy is frequently compromised by dose-limiting nephrotoxicity. Approximately 30% of patients receiving cisplatin develop acute kidney injury (AKI), which increases the risk of chronic kidney disease (CKD), a leading cause of morbidity and mortality. Despite extensive preclinical efforts, no FDA-approved therapy currently exists to prevent or treat cisplatin-induced nephrotoxicity (CIN). This in part is due to the reliance of preclinical studies on non-cancer animal models that fail to capture the complex physiological alterations associated with malignancy. To address this limitation, we developed a clinically relevant model in …

Do Finances Determine Our Fate?: Understanding The Relationships Between Socioeconomic Status, Inflammation, And Cancer Recurrence Risk, Faith Wilbourne

Master's Theses

Individuals of a low socioeconomic status (SES) are more likely to experience a cancer recurrence relative to individuals with a higher SES. This may be partially explained by the stressors of living with a low SES. These stressors can increase inflammatory markers known to elevate the risk of cancer development. Health-promoting behaviors such as exercise, adequate sleep, and a healthy diet can reduce systemic inflammation. Health behaviors may therefore moderate any potential relationship between SES and cancer recurrence risk. This study explored associations between SES (income, educational attainment) and inflammatory markers related to cancer recurrence while seeking to determine if …

Exploring The Mechanisms Of Varicella-Zoster Virus Pathogenesis And Its Potential Role In Oncogenesis, Fernando Cisneros, Blake Martin

Research Symposium

Background: Varicella-zoster virus (VZV) is a highly prevalent pathogen primarily recognized for causing chickenpox during primary infection and herpes zoster (HZ), also known as shingles, upon reactivation. While post-infectious complications of VZV, such as encephalitis, pneumonia, and post-herpetic neuralgia, are well-established, recent large population-based studies suggest that HZ may increase the risk of occult cancers. Emerging evidence suggests that VZV may modulate key oncogenic pathways, such as the inhibition of apoptosis, alteration of cell cycle regulatory enzymes, and interference with immunosurveillance, which could potentially promote cancer development. These findings indicate that VZV’s role in cancer biology may involve direct cellular …

Use Of Immunoglobulin Replacement Therapy In Clinical Practice: A Review, Jibran Ahmed, Yeonjoo Choi, Taeyeong Ko, Joann Lim, Joud Hajjar

Faculty, Staff and Students Publications

Immunoglobulins (Igs) are produced by B lymphocytes and play a key role in humoral immunity. Igs are classified into five isotypes (IgG, IgA, IgM, IgE, and IgD). Their primary function is to recognize and bind to foreign antigens. When Igs bind to antigens, they facilitate phagocytosis and promote clearance mediated by other immune cells. It is an essential component in protecting the host from outside pathogens. Hypogammaglobulinemia predisposes an individual to severe and recurrent infections. Therefore, replacement therapy is recommended to maintain optimal Ig level. In addition, Igs can modulate immune responses by to neutralizing proteins such as endotoxins or …

Immune Pathway Modulation In Melanoma Using Chitosan Nanoparticle-Mediated Dsrna Delivery, Bethel C. Iwuji

Theses and Dissertations (Comprehensive)

Cancer is a group of diseases characterized by abnormal and uncontrolled cell division, which typically results in the formation of tumours. Even with advances in treatments, cancer remains one of the leading causes of death globally. Melanoma is an aggressive form of skin cancer which is highly malignant, develops in the pigment-producing cells of the skin, melanocytes, and in the late stages of the disease poses a significant challenge for therapeutic intervention due to its multidrug resistance. The innate immune system is the first line of defence against invading pathogens, including viruses, bacteria, and fungi, and can recognize and destroy …

Combination Therapy Of Ido1 Inhibition And Anti-Pd1 Mediates Anti-Tumor Immunity By Promoting Memory Immunity Development And Cytotoxicity Of Γδ T And Nk Cells Via Il-2 Signaling And By Overcoming Pro-Tumor Effects Of Tgf-Β Signaling, Hyuk Jee

Dartmouth College Master’s Theses

Cutaneous melanoma is the most aggressive form of skin cancer even though it takes only about 1% of all skin cancers. Even among all cutaneous melanomas, NRAS-mutant melanoma is more aggressive than any other, and about 10-25% of all cutaneous melanoma cases have mutations in NRAS. NRAS is a member of the RAS family of proto-oncogenic GTPase proteins, and it plays a key role in signal transduction pathways responsible for cellular survival, proliferation, and metabolism. Immunotherapy is the first line of defense against NRAS-mutant melanoma because, despite tremendous efforts made for decades, it has not been successful to develop small …

Gut Microbial Dysbiosis Differs In Two Distinct Cachectic Tumor-Bearing Models Consuming The Same Diet, Lauri O. Byerley, Brittany Lorenzen, Hsiao Man Chang, William G. Hartman, Michael J. Keenan, Ryan Page, Meng Luo, Scot E. Dowd, Christopher M. Taylor

School of Medicine Faculty Publications

The impact of cancer cachexia on the colonic microbiota is poorly characterized. This study assessed the effect of two cachectic-producing tumor types on the gut microbiota to determine if a similar dysbiosis could be found. In addition, it was determined if a diet containing an immunonutrient-rich food (walnuts) known to promote the growth of probiotic bacteria in the colon could alter the dysbiosis and slow cachexia. Male Fisher 344 rats were randomly assigned to a semi-purified diet with or without walnuts. Then, within each diet group, rats were further assigned randomly to a treatment group: tumor-bearing ad libitum fed (TB), …

Epstein-Barr Virus-Based Prognostic Model In Nodular Sclerosis Classic Hodgkin Lymphoma, Chen Jiang, Li-Yun Huang, Ji-Hao Zhou, Zhi-Ming Li, Yu Wang, Shuo Li, Jian-Chang Fu, Qi-Tao Huang, Qin Yan, Yu-Yuan Huang, Min Zuo, Shimin Hu, Robert Peter Gale, Yang Liang, Jing-Ping Yun, Yu-Hua Huang

Faculty, Staff and Student Publications

The role of Epstein-Barr virus (EBV) in lymphoma cells of nodular sclerosis classic Hodgkin lymphoma (NScHL) is controversial. Our aim was to explore this and establish a clinically feasible model for risk stratification. We interrogated data from 542 consecutive subjects with NScHL receiving ABVD therapy and demonstrated EBV-infection in their lymphoma cells with EBV-encoded small RNAs (EBERs) in situ hybridization. Subjects were divided into training and validation datasets. As data from the training dataset suggested EBERs-positivity was the only independent prognostic factor for both progression-free survival (PFS) and overall survival (OS), we developed corresponding prognostic models based on it. Our …

Timigp: An R Package To Depict The Tumor Microenvironment From Bulk Transcriptomics, Chenyang Li, Jianjun Zhang, Chao Cheng

Faculty, Staff and Students Publications

Exploring the clinical relevance of diverse immune cell types within the tumor microenvironment is pivotal for unraveling cancer intricacies and developing treatments. Here, we present a protocol for using tumor immune microenvironment illustration based on gene pairs, an R package to deduce cell-cell interactions, unveiling the association between immune cell relative abundance and patient prognoses from bulk gene expression and survival data. We describe steps for harnessing cell-type markers derived from single-cell RNA sequencing data to map the tumor immune microenvironment across a spectrum of cancer types. For complete details on the use and execution of this protocol, please refer …

Pediatric Hiv+ Kaposi Sarcoma Exhibits Clinical, Virological, And Molecular Features Different From The Adult Disease, Carolina Caro-Vegas, Alice Peng, Angelica Juarez, Allison Silverstein, William Kamiyango, Jimmy Villiera, Casey L Mcatee, Rizine Mzikamanda, Tamiwe Tomoka, Erin C Peckham-Gregory, Razia Moorad, Carrie L Kovarik, Liane R Campbell, Parth S Mehta, Peter N Kazembe, Carl E Allen, Michael E Scheurer, Nmazuo W Ozuah, Dirk P Dittmer, Nader Kim El-Mallawany

Center for Medical Ethics and Health Policy Staff Publications

BACKGROUND

Kaposi sarcoma (KS) is among the most common childhood cancers in Eastern and Central Africa. Pediatric KS has a distinctive clinical presentation compared with adult KS, which includes a tendency for primary lymph node involvement, a considerable proportion of patients lacking cutaneous lesions, and a potential for fulminant disease. The molecular mechanisms or correlates for these disease features are unknown.

METHODS

This was a cross-sectional study. All cases were confirmed by IHC for KS-associated herpesvirus (KSHV) LANA protein. Baseline blood samples were profiled for HIV and KSHV genome copy numbers by qPCR and secreted cytokines by ELISA. Biopsies were …

Anticancer Drug Screening Using Invitro Cell Proliferation Assay, Kristopher L. Ezell, Kyle Doxtater, Samantha Lopez, Sophia M. Leslie, Justin Wendel, Kamaldeep Paul, Vijay Lauxmi, Manish Tripathi

Research Colloquium

Introduction: In this presentation cell proliferation methods and how they are related to screening for effective chemotherapy drugs will be reviewed. Cancer in its most basic form is the unchecked mass dividing of cells while normal apoptosis is not undertaken for various reasons, some of which that have yet to be discovered. By these means’ tumors form that inhibit the functions of the organs it is residing in and the effected cells may metastasize and spread throughout the body. For this reason, chemotherapy drugs must be assessed through introduction into working strains of cultured cancer cells that are then screened …

Oral Delivery Of Rnai For Cancer Therapy, Humayra Afrin, Renu Geetha Bai, Raj Kumar, Sheikh Shafin Ahmad, Sandeep K Agarwal, Md Nurunnabi

Faculty, Staff and Students Publications

Cancer is a major health concern worldwide and is still in a continuous surge of seeking for effective treatments. Since the discovery of RNAi and their mechanism of action, it has shown promises in targeted therapy for various diseases including cancer. The ability of RNAi to selectively silence the carcinogenic gene makes them ideal as cancer therapeutics. Oral delivery is the ideal route of administration of drug administration because of its patients' compliance and convenience. However, orally administered RNAi, for instance, siRNA, must cross various extracellular and intracellular biological barriers before it reaches the site of action. It is very …

Development Of Combination Therapy Strategies To Treat Cancer Using Dihydroorotate Dehydrogenase Inhibitors, Nicholas Mullen

Theses & Dissertations

Cancer cells require supraphysiologic levels of nucleotide triphosphates to fuel their malignant behaviors, including uncontrolled proliferation, immune evasion, metastasis, and therapy resistance. This requirement is met by hyperactive flux through the de novo pyrimidine and de novo purine pathways. Dihydroorotate dehydrogenase (DHODH) is an essential enzyme in the de novo pyrimidine pathway that can be targeted by FDA approved and experimental drug compounds. A robust body of preclinical evidence, encompassing hundreds of independent studies over several decades, demonstrates impressive activity of DHODH inhibitors in animal models of cancer. Paradoxically, however, all clinical trials to date have failed to demonstrate efficacy …

Fucosylation Of Hla-Drb1 Regulates Cd4+ T Cell-Mediated Anti-Melanoma Immunity And Enhances Immunotherapy Efficacy, Daniel K Lester, Chase Burton, Alycia Gardner, Patrick Innamarato, Krithika Kodumudi, Qian Liu, Emma Adhikari, Qianqian Ming, Daniel B Williamson, Dennie T Frederick, Tatyana Sharova, Michael G White, Joseph Markowitz, Biwei Cao, Jonathan Nguyen, Joseph Johnson, Matthew Beatty, Andrea Mockabee-Macias, Matthew Mercurio, Gregory Watson, Pei-Ling Chen, Susan Mccarthy, Carlos Moransegura, Jane Messina, Kerry L Thomas, Lancia Darville, Victoria Izumi, John M Koomen, Shari A Pilon-Thomas, Brian Ruffell, Vincent C Luca, Robert S Haltiwanger, Xuefeng Wang, Jennifer A Wargo, Genevieve M Boland, Eric K Lau

Faculty, Staff and Student Publications

Immunotherapy efficacy is limited in melanoma, and combinations of immunotherapies with other modalities have yielded limited improvements but also adverse events requiring cessation of treatment. In addition to ineffective patient stratification, efficacy is impaired by paucity of intratumoral immune cells (itICs); thus, effective strategies to safely increase itICs are needed. We report that dietary administration of l-fucose induces fucosylation and cell surface enrichment of the major histocompatibility complex (MHC)-II protein HLA-DRB1 in melanoma cells, triggering CD4+ T cell-mediated increases in itICs and anti-tumor immunity, enhancing immune checkpoint blockade responses. Melanoma fucosylation and fucosylated HLA-DRB1 associate with intratumoral T cell abundance …

Identifying Biomarkers Of Differential Chemotherapy Response In Tnbc Patient-Derived Xenografts With A Ctd/Wgcna Approach, Varduhi Petrosyan, Lacey E Dobrolecki, Lillian Thistlethwaite, Alaina N Lewis, Christina Sallas, Ramakrishnan R Srinivasan, Jonathan T Lei, Vladimir Kovacevic, Predrag Obradovic, Matthew J Ellis, C Kent Osborne, Mothaffar F Rimawi, Anne Pavlick, Maryam Nemati Shafaee, Heidi Dowst, Antrix Jain, Alexander B Saltzman, Anna Malovannaya, Elisabetta Marangoni, Alana L Welm, Bryan E Welm, Shunqiang Li, Gerburg M Wulf, Olmo Sonzogni, Chen Huang, Suhas Vasaikar, Susan G Hilsenbeck, Bing Zhang, Aleksandar Milosavljevic, Michael T Lewis

Faculty, Staff and Students Publications

Although systemic chemotherapy remains the standard of care for TNBC, even combination chemotherapy is often ineffective. The identification of biomarkers for differential chemotherapy response would allow for the selection of responsive patients, thus maximizing efficacy and minimizing toxicities. Here, we leverage TNBC PDXs to identify biomarkers of response. To demonstrate their ability to function as a preclinical cohort, PDXs were characterized using DNA sequencing, transcriptomics, and proteomics to show consistency with clinical samples. We then developed a network-based approach (CTD/WGCNA) to identify biomarkers of response to carboplatin (MSI1, TMSB15A, ARHGDIB, GGT1, SV2A, SEC14L2, SERPINI1, ADAMTS20, DGKQ) and docetaxel (c, MAGED4, …

A Bibliometric And Visual Analysis Of Cancer-Associated Fibroblasts, Wei-Chen Yuan, Jie-Xiang Zhang, Hai-Bin Chen, Ying Yuan, Yu-Pei Zhuang, Hong-Li Zhou, Mu-Han Li, Wen-Li Qiu, Hong-Guang Zhou

Faculty, Staff and Student Publications

Background: Cancer-associated fibroblasts (CAFs) represent the predominant stromal component within the tumour microenvironment (TME), exhibiting considerable heterogeneity and plasticity that significantly impact immune response and metabolic reprogramming within the TME, thereby influencing tumour progression. Consequently, investigating CAFs is of utmost importance. The objective of this study is to employ bibliometric analysis in order to evaluate the current state of research on CAFs and predict future areas of research and emerging trends.

Methods: Conduct a comprehensive search for scholarly publications within the Web of Science Core Collection database, encompassing the time period from January 1, 2001, to December 31, 2022. Apply …

Hypoxia Regulates Vessel-Modifying Macrophages And Vice Versa In Tumors, Kayla Jo Steinberger

Graduate Theses, Dissertations, and Problem Reports (ETD)

Hypoxia, or low oxygen, is a common feature of solid tumors correlating with poor survival in cancer patients. Growing tumors need a blood supply to deliver oxygen. Tumors attempt to re-acquire oxygen by forming new blood vessels from nearby, pre-existing vessels, a process known as angiogenesis. Past treatments aimed at preventing this process yielded not only disappointing results in the clinic but sometimes worsened the patient’s prognosis making the tumor more hypoxic, emphasizing the urgent need for novel targets. In tumors, angiogenesis is notoriously dysfunctional resulting in leaky, under-perfused blood vessels which cannot adequately deliver oxygen and exacerbates hypoxia. Emerging …

Detailing The Effects Of Cbd On Parp And Survivin Expression In Ewing Sarcoma, Tyler Carter

Theses

Ewing sarcoma (ES) is an aggressive pediatric bone cancer with low five-year survival rates, particularly with recurrent disease because ES often becomes resistant to chemotherapy in these recurrences. Cannabidiol (CBD) has been identified as a potentially promising therapeutic for patients with ES. In other cancer types, CBD has demonstrated effects on two major proteins that contribute to chemotherapy resistance. The first, Poly (ADP-ribose) Polymerase I (PARP1), is a DNA damage repair enzyme that is overexpressed in recurrent ES. Though chemotherapy induces DNA damage in these cancer cells, the high levels of PARP1 facilitate repair of the DNA, allowing the mutated …

Defining The Cooperation Between Mhc-I And Mhc-Ii Neoantigen-Driven T Cell Responses To Develop Effective Personalized Immunotherapies, Charmelle Williams

Dissertations and Theses (Open Access)

Immune checkpoint therapy (ICT) (e.g. anti-CTLA-4 (α-CTLA-4), anti-PD-1 (α-PD-1)) enables durable T cell-dependent anti-tumor immunity in certain cancer patients. Since a subset of patients respond to ICT, this work aims at developing a more in-depth understanding of T-cell responses to MHC class I (MHC-I) and MHC class II (MHC-II) tumor antigens that are derived from aberrant expression of non-mutant antigens or driver and passenger somatic alterations that can function as tumor neoantigens. We used a poorly immunogenic Braf^v600e Pten^-/- Cdkn2a^-/- YUMM1.7 (Y1.7) murine melanoma line with a paucity of endogenous neoantigens that is unresponsive to ICT, and …

Antigen Staining For Detection Of Muc13 And Muc16 Expression In Carcinoma Tissue, Jose A. Benitez

MEDI 9331 Scholarly Activities Clinical Years

MUC13 and MUC16 are epithelial expressed proteins implicated in various carcinomas. Overexpression of these biomarkers appear to play a role in tumor growth; this discovery has paved a road for multiple studies discussing the potential of targeting mucin proteins and optimize immunotherapy approaches against carcinomas. Our study serves to investigate the level of expression of MUC13 and MUC16 in cancerous and normal tissue and to discuss the implications our findings may have for the utilization of these biomarkers for cancer therapy.

T Cell Therapy: Underlying Mechanisms And Current Advancements, Griffin Mccloy

Senior Honors Theses

As the second leading cause of death in 2016, cancer is one of the most serious diseases facing the world today. T cell therapy is a current area of research attempting to address the disease with two primary division: CAR-T and TCR-T cell therapy. The immune system naturally produces T lymphocytes to aid in the recognition and removal of cells infected with viruses or transformed into cancer. Under normal circumstances, T lymphocytes identify and destroy cancerous cells; however, some cancerous cell types can evade this system. With the use of genetic editing technology, T lymphocytes can gain the ability to …

The Effects Of Glucocorticoids And Immunosuppressants On Cancer Outcomes In Checkpoint Inhibitor Therapy, Sebastian Bruera, Maria E Suarez-Almazor

Faculty, Staff and Students Publications

The emergence of checkpoint inhibitors has created a paradigm shift for the treatment of various malignancies. However, although these therapies are associated with improved survival rates, they also carry the risk of immune-related adverse events (irAEs). Moderate to severe irAEs are typically treated with glucocorticoids, sometimes with the addition of immunosuppressants as steroid-sparing therapy. However, it is unclear how glucocorticoids and immunosuppressants may impact cancer survival and the efficacy of immune checkpoint therapy on cancer. In this narrative review, we discuss the effects of glucocorticoids and immunosuppressants including methotrexate, hydroxychloroquine, azathioprine, mycophenolate mofetil, tumor-necrosis factor (TNF)-inhibitors, interleukin-6 inhibitors, interleukin-1 inhibitors, …

Cytomegalovirus Infection Among Patients With Cancer Receiving Immune Checkpoint Inhibitors, Kavea Panneerselvam, David Szafron, Rajan N Amin, Dongguang Wei, Dongfeng Tan, Mehmet Altan, Pablo C Okhuysen, Malek Shatila, Gottumukkala Subba Raju, Anusha S Thomas, Yinghong Wang

Faculty, Staff and Students Publications

BACKGROUND: Immune checkpoint inhibitors (ICIs), used for the treatment of solid and hematologic malignancies, come with the risk of immune-related adverse events (irAEs). Opportunistic infections (e.g., cytomegalovirus [CMV]) mimic irAE symptoms and are understudied in this population. We aimed to describe the incidence, characteristics, treatment and outcomes of CMV infection in ICI-treated patients.

METHODS: We conducted a single-center retrospective review of all adult patients who were CMV-positive after ICI therapy between 06/2011 and 05/2020. A CMV-positive non-ICI cohort was matched to the ICI group based on age, sex and cancer type. Variables of interest were collected through electronic medical records. …

The Investigations Of Nps Modulated Immunity And Immunometabolism, Brittney Leigh Ruedlinger

Biomedical Sciences Theses & Dissertations

Cancers remain in the top noncommunicable diseases responsible for premature mortality. The heterogeneity among cancers and within tumors makes treating them ever more challenging. Our misfortune for developing cures is mocked by cancer, with the lowest probability of success (PoS) through clinical trials and FDA approval. At the basic level, there are generally two broad gaps impeding cancer eradication: the unidentified shared mechanism(s) exploited by all cancers and the therapeutic approach to intervene. Nanosecond pulse stimulation (NPS) offers a unique approach since its broad impacts intersect those often hijacked by oncogenesis. Metabolic pathways, known for dysfunctions among cancers, share a …

Evaluating The Microbial Experience Influence On Anti-Tumor Immune Response, Jessica A. Ensing

Student Summer Scholars Manuscripts

Despite the steady increase of hygienic standards, the CDC continues to report an increase of immune-mediated diseases such as allergies and asthma. Human avoidance of microbial exposure and subsequently less experienced immune systems may be the cause for this increase. We investigated if increased microbial exposure results in increased immunity to cancer (B16 melanoma) by measuring activated lymphocytes between two groups of C57Bl/6 mice: specific pathogen free (SPF) mice (which had little microbial exposure) and cohoused (COH) mice (which were exposed to numerous microbes). Previous research shows that the CoH mouse model mimics a human adult’s immune system, while the …

Identification Of A Novel Single Amino Acid Substitution (V666g) Of Jak1 From A Patient With Acute Lymphoblastic Leukemia Impairs Jak3 Mediated Il-2 Signaling, Alice Hernandez Grant

Open Access Theses & Dissertations

The Janus kinase (JAK) family, notably JAK1, JAK2 and JAK3 are recognized as oncogenic drivers in high risk Acute Lymphoblastic Leukemia (ALL). The bulk of activating JAK mutations are thought to occur within functional hot-spots across Janus Homology (JH) domains. The most frequently mutated regions is the JH2 pseudo-kinase, which provides a negative regulatory role to the adjacent catalytically active JH1 kinase domain. Despite the prevalence of JAK activating mutations and a need for new therapeutic inhibitors, there is a lack of understanding in the allosteric regulation of JAK kinases. Here we sought to identify mutations involved in driving ALL …

The Stimulation Of Dendritic Cells By Cationic Lipids, John Peyton Bush

Theses and Dissertations--Medical Sciences

The discovery that cationic lipids can independently stimulate the immune system has generated interest in their potential as vaccine adjuvants. Here, we show that the cationic lipid R-DOTAP can independently stimulate type 1 interferon production in dendritic cells in both primary culture and immortalized cell culture. Levels of type 1 interferon production are cell line-dependent and limited in vitro by lipid-induced cell death. We show that cationic lipids can independently activate TLR-7 and TLR-9, suggesting a mechanism for type 1 interferon induction. This TLR-stimulatory activity is not restricted to R-DOTAP and can be extended to other similar cationic lipids in …

Generation, Identification And Characterization Of Novel Monoclonal Antibodies Against Ctla-4, Pd-1 And Btla For The Treatment Of Cancer, Rosabril Acuna

Open Access Theses & Dissertations

Members of the CD28 co-inhibitory receptor family, Cytotoxic T-lymphocyte- associated antigen 4 (CTLA-4), Program death-1 (PD-1) and B- and T-lymphocyte attenuator (BTLA) are type I transmembrane proteins expressed on a variety of immune cells. Co- inhibitory receptors deliver "off" signals that play an important role in down regulating immune cell activation. Manipulation of inhibitory signals have shown to be a powerful strategy in the treatment of autoimmune diseases, infectious diseases and various forms of cancer. In fact, the FDA (Food and Drug Administration) has approved the use of monoclonal antibodies against CTLA-4 (Ipilimumab) for the treatment of metastatic melanoma, against …

Roles Of Cytosolic Nucleic Acid Sensors In Cancer And Infection, Qifan Zhu

Theses and Dissertations (ETD)

Pattern recognition receptors are innate immune sensors that recognize pathogen-associated molecular patterns (PAMPs) and danger-associated molecular patterns (DAMPs) with crucial roles in host defense against microbial infection, autoimmune diseases and cancer. Cytosolic nucleic acids including DNA and RNA originate from pathogens or self-cells, which form major groups of PAMPs and DAMPs. A range of nucleic acid sensors have evolved to sense various types of nucleic acids. How different DNA-sensing pathways regulate microbial infection and cancer is the focus of this dissertation.

Stimulator of IFN genes (STING) is a cytosolic innate immune sensor for cyclic dinucleotides that also serves a dual …