Allergy and Immunology Commons^™

Uncovering The Role Of Cancer Associated Fibroblasts In Tumor Immunosuppression, Kamal Amirneni, Kavitha Yaddanapudi

Posters-at-the-Capitol

Current advances in cancer immunotherapy are hindered by the immunosuppressive nature of the tumor microenvironment (TME). Cancer-associated fibroblasts (CAFs) are a key component of the TME that contribute to suppressing the immune response. Chemokines and cytokines released by CAFs, such as IL-6, attract circulating monocytes which are converted into myeloid-derived suppressor cells (MDSCs). MDSCs suppress T-cells and natural killer cell proliferation which inactivates the immune response and deters immunotherapy. Both Prostaglandin E₂ (PGE₂) and granulocyte-macrophage colony-stimulating factor (GM-CSF) have been implicated in the CAF immunosuppressive pathway, but a causal link has yet to be established. We hypothesized …

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

Dissertations & 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 …

Real-World Third Covid-19 Vaccine Dosing And Antibody Response In Patients With Hematologic Malignancies, Michael A. Thompson, Sigrun Hallmeyer, Veronica E. Fitzpatrick, Yunqi Liao, Michael P. Mullane, Stephen C. Medlin, Kenneth Copeland, James L. Weese

Journal of Patient-Centered Research and Reviews

Purpose: This study sought to describe the changes in immune response to a third dose of either Pfizer’s or Moderna’s COVID-19 mRNA vaccine (3V) among patients with hematologic malignancies, as well as associated characteristics

Methods: This retrospective cohort study analyzed pre-3V and post-3V data on 493 patients diagnosed with hematologic malignancies across a large Midwestern health system between August 28, 2021, and November 1, 2021. For antibody testing, S1 spike antigen of the SARS-CoV-2 virus titer was used to determine serostatus.

Results: Among 493 participants, 274 (55.6%) were seropositive both pre- and post-3V (+/+) while 115 (23.3%) seroconverted to positive …

Gender Differences In Urothelial Bladder Cancer: Effects Of Natural Killer Lymphocyte Immunity, Charles T. Lutz, Lydia Livas, Steven R. Presnell, Morgan Sexton, Peng Wang

Pathology and Laboratory Medicine Faculty Publications

Men are more likely to develop cancer than women. In fact, male predominance is one of the most consistent cancer epidemiology findings. Additionally, men have a poorer prognosis and an increased risk of secondary malignancies compared to women. These differences have been investigated in order to better understand cancer and to better treat both men and women. In this review, we discuss factors that may cause this gender difference, focusing on urothelial bladder cancer (UBC) pathogenesis. We consider physiological factors that may cause higher male cancer rates, including differences in X chromosome gene expression. We discuss how androgens may promote …

Exploring The Role Of Nkr-P1b:Clr-B Interaction In Mouse Mammary Tumour Immunosurveillance, Raghd Al Olabi

Electronic Theses and Dissertations

Natural killer (NK) cells are large, granular, and cytotoxic innate lymphocytes which do not require prior antigenic exposure to target cancerous and virally infected cells. NK cells possess activating and inhibitory receptors which may activate or inhibit NK cell activity, respectively. In mice, the inhibitory NKR-P1B receptor on NK cells recognizes the C-type lectin-related protein-b (Clr-b) ligand expressed on most autologous cells but downregulated on many tumour cell lines. In B cell lymphoma models, the disruption of NKR-P1B:Clr-b interaction results in delayed tumour development and progression, suggesting that blockage of inhibitory signals from NKR-P1B augments NK cell activity against lymphoma …

Etv2/Myct1 Axis In The Regulation Of Tumor Angiogenesis And Anti-Tumor Immunity, Ashraf Ul Kabir

Arts & Sciences Electronic Theses and Dissertations

Angiogenesis is a critical determinant of neoplastic growth and metastatic spread. As such, anti-angiogenic approaches have long been tried to throttle down tumor progression. However, current anti-angiogenic treatments so far have produced modest clinical benefits. Further in-depth research has provided rationales behind these disappointing and apparent perplexing clinical outcomes. It is now established that VEGF (vascular endothelial growth factor) and other prominent current angiogenic targets are neither specific to the vascular system nor the pathological conditions explaining the sub-optimal angiogenic control following the existing treatments. This suggests that anti-angiogenesis could still be a viable strategy for cancer patients should there …

Mechanisms Of Natural Killer Cell Anti-Tumor Function And Homeostasis, Julia Alexandra Wagner

Arts & Sciences Electronic Theses and Dissertations

Natural killer (NK) cells are innate lymphoid cells (ILCs) that mediate anti-tumor and anti-viral immune responses. They do so via two primary effector functions: cytokine production and direct cytotoxicity. Unlike adaptive T and B lymphocytes, NK cells do not rearrange their DNA to express a predominant antigen-specific receptor, and instead express a variety of stochastically-expressed, germline DNA-encoded activating and inhibitory receptors whose signals integrate to govern their functional responses. What results is a diverse repertoire of NK cells capable of recognizing a variety of malignantly-transformed or virally-infected cells. Studies from several groups have established the anti-tumor potential of NK cells, …

Research Amidst The Pandemic, Howard Burris

HCA Healthcare Journal of Medicine

Cancer patients need access to promising investigational therapies, available only through clinical trials, and the emergence of COVID-19 and the resulting pandemic became an emerging threat to fulfilling that need. Many academic medical centers were pausing their clinical research programs, diverting their resources and sheltering their teams. Sarah Cannon, the Cancer Institute of HCA Healthcare, made the decision to stay safe, but stay the course.

Selecting The Optimal Unrelated Hematopoietic Stem Cell Transplant Donor For Relapse Prevention In Acute Myeloid Leukemia, Elizabeth Krieger, Rehan Qayyum, Amir Toor

Graduate Medical Education (GME) Resident and Fellow Research Day Posters

Introduction/Background

Hematopoietic cell transplantation (HCT) provides

a cure for patients with acute myeloid leukemia.

Natural killer cells (NK) play an important role

in graft versus leukemia (GVL) effect after HCT,

through killer immunoglobulin-like receptor (KIR)

interaction with HLA ligands. This study is

undertaken to validate our previously published

mathematical model accounting for the KIR-KIRL

interactions in a post HCT setting.

Methods

Retrospective data were obtained from the Center

for International Blood and Marrow Transplant

Registry for 2317 donor recipient pairs (DRP) who

underwent 7/8 or 8/8 HLA allelic matched

unrelated donor (URD) HCT for AML. KIR-HLA

interaction scores were calculated …

T Cell Immunity In Pancreatic Cancer Is Undermined By Dendritic Cell Dysfunction, Samarth Hegde

Arts & Sciences Electronic Theses and Dissertations

Pancreatic cancer carries a dismal prognosis, and desperately needs viable therapeutic interventions beyond chemo-radiation. T cell-dependent immunotherapies have shown great promise in several tumor types, but have not been effective for the vast majority of pancreatic cancer patients. This is, in part, due to our limited understanding of how antigenicity of pancreatic lesions is recognized, and how adaptive immunity is overcome in this disease. We sought to study tumor-immune interactions and identify mechanisms for this immune-failure using several spontaneous and unperturbed mouse models of pancreatic adenocarcinoma. We found that early pancreatic lesions fail to elicit tumor-limiting CD4+ TH1 and CD8+ …

The Dna Methyltransferase Inhibitor, Guadecitabine, Targets Tumor-Induced Myelopoiesis And Recovers T Cell Activity To Slow Tumor Growth, Andrea J. Elkovich

Theses and Dissertations

Myeloid Derived Suppressor Cells (MDSC) represent a significant hurdle to cancer immunotherapy because they dampen anti-tumor cytotoxic T cell responses. Previous studies have reported on the myelo-depletive effects of certain chemotherapies. Using guadecitabine, a next-generation DNA methyltransferase inhibitor (DNMTi), we observed significantly reduced tumor burden in the 4T1 murine mammary carcinoma model. Guadecitabine treatment prevents excessive tumor-induced myeloid proliferation and systemic accumulation, and skews remaining MDSCs toward a beneficial antigen-presenting phenotype. Together, this alters the splenic environment to improve T cell activation and interferon-gamma (IFNg) production. Additionally, guadecitabine enhances the therapeutic effect of adoptively transferred antigen-experienced lymphocytes to diminish tumor …

Development Of A Pd-L1 Pet Imaging Biomarker, Caleb Jack Bridgwater

Posters-at-the-Capitol

Immunotherapy strategies are very promising treatments for cancer patients. Specifically, Immune checkpoint inhibitor therapy focusing on the PD-1/PD-L1 pathway shows long-lasting positive results in many cancer patients. Unfortunately, not all the patients can benefit from this highly effective treatment. Hence, there is a great need for predictive biomarkers. Immunohistochemical (IHC) staining has been used as a way of predicting patient response, yet shows many problems. For example, IHC utilizes an invasive biopsy and sample fixing, which creates an incomplete and delayed picture of the patient’s biochemistry and the tumor microenvironment, consequently ignoring metastases.

The purpose of this study is to …

Tumors Interrupt Irf8-Mediated Dendritic Cell Development To Overcome Immune Surveillance, Melissa Ann Meyer

Arts & Sciences Electronic Theses and Dissertations

Tumors employ multiple mechanisms to evade immune surveillance. One mechanism is tumor-induced myelopoiesis, which expands immune suppressive granulocytes and monocytes to create a protective tumor niche shielding even antigenic tumors. As myeloid cells and immune-stimulatory conventional dendritic cells (cDCs) are derived from the same progenitors, it is logical that tumor-induced myelopoiesis might also impact cDC development. The cDC subset cDC1 is marked by CD141 in humans and CD103 or CD8α in mice. cDC1s act by cross presenting antigen and activating CD8+ T cells. Given these functions, CD103+ cDC1s can support anti-tumor CD8+ T cell responses. However, CD103+ cDC1 numbers are …

Evaluation And Adaptation Of Live-Cell Interferometry For Applications In Basic, Translational, And Clinical Research, Kevin A. Leslie

Theses and Dissertations

Cell mass is an important indicator of cell health and status. A diverse set of techniques have been developed to precisely measure the masses of single cells, with varying degrees of technical complexity and throughput. Here, the development of a non-invasive, label-free optical technique, termed Live-Cell Interferometry (LCI), is described. Several applications are presented, including an evaluation of LCI’s utility for assessing drug response heterogeneity in patient-derived melanoma lines and the measurement of CD3+ T cell kinetics during hematopoietic stem cell transplantation. The characterization of mast cells during degranulation, the measurement of viral reactivation kinetics in Kaposi’s Sarcoma, and drug …

Managing Toxicities Associated With Immune Checkpoint Inhibitors: Consensus Recommendations From The Society For Immunotherapy Of Cancer (Sitc) Toxicity Management Working Group., I. Puzanov, A. Diab, K. Abdallah, C. O. Bingham, C. Brogdon, R. Dadu, L. Hamad, S. Kim, M. E. Lacouture, N. R. Leboeuf, D. Lenihan, C. Onofrei, V. Shannon, R. Sharma, A. W. Silk, D. Skondra, M. E. Suarez-Almazor, Y. Wang, K. Wiley, H. L. Kaufman, M. S. Ernstoff, J. Anderson, K. Lehman, D. Reshef, A. Saylors, M. Turner, I. Waxman, D. Arrindell, S. Andrews, J. Ballesteros, J. Boyer, I. Cotarla, M. Dawson, T. Goswami, V. Hayreh, W. Holmes, Z. Rasheed, M. Sarkeshik, J. Schreiber, K. Shafer-Weaver, D. Chen, S. Ley-Acosta, D. Chonzi, W. Go, R. Cunha, J. L. Gulley, L. Wood, M. Davies, Adam Dicker, L. Eifler, N. Gregory, A. Ferguson, C. Ferlini, S. Frankel, C. Gochett, J. Goldberg, K. Patel, D. Wariabharaj, P. Goncalves, N. Helie, J. Y. Hsu, R. Ibrahim, C. Larocca, O. Lambotte, J. Luke, J. Mcclure, E. Michelon, M. Nakamura, B. Piperdi, J. Riemer, C. Robert, W. Sharfman, E. Sharon, R. Sherry, C. Simonson, C. Thomas, E. Trehu, J. A. Thompson, D. Tresnan, L. Zhang, P. Zheng

Department of Radiation Oncology Faculty Papers

Cancer immunotherapy has transformed the treatment of cancer. However, increasing use of immune-based therapies, including the widely used class of agents known as immune checkpoint inhibitors, has exposed a discrete group of immune-related adverse events (irAEs). Many of these are driven by the same immunologic mechanisms responsible for the drugs' therapeutic effects, namely blockade of inhibitory mechanisms that suppress the immune system and protect body tissues from an unconstrained acute or chronic immune response. Skin, gut, endocrine, lung and musculoskeletal irAEs are relatively common, whereas cardiovascular, hematologic, renal, neurologic and ophthalmologic irAEs occur much less frequently. The majority of irAEs …

Improving Nk Cell Therapy For Osteosarcoma, Jennifer Foltz

Dissertations & Theses (Open Access)

Osteosarcoma (OS) is the most common primary bone tumor. Despite new treatment options, 5-year survival for metastatic OS has remained at only 30% for the last 30 years. Adoptive transfer of Natural Killer (NK) cells holds promise for a new, non-toxic therapy for OS. NK cells are part of the innate immune system and readily kill metastatic and chemotherapy-resistant OS in vitro and in murine models. However, there is little data regarding their efficacy in animal models with an intact immune system. In addition, the OS tumor microenvironment is highly suppressive, producing TGFβ which impedes NK cell killing of solid …

Defining The Ontogeny And Functions Of Macrophages In Pancreatic Ductal Adenocarcinoma, Yu Zhu

Arts & Sciences Electronic Theses and Dissertations

The immune system plays an essential role in protecting the host organisms against both foreign invaders and self-attacks arisen within the host, such as tumors. Instead of promoting the long-term fitness of the organism, the immune system is often suppressed or hijacked by tumor cells to accelerate the progression of malignancies. Among the key drivers of immune suppression, macrophages are one of the most abundant immune cells present in tumor tissues. High levels of macrophage infiltration in the malignant tissues correlate with negative patient outcome in many types of cancers, including pancreatic ductal adenocarcinoma (PDAC), one of the most lethal …

Characterization Of Murine Breast Cancer Cell Lines For Anti-Cancer Vaccine, Haven N. Frazier

Biological Sciences Undergraduate Honors Theses

Breast cancer is the most commonly diagnosed cancer in women and the second leading cause of cancer death among women in the United States (1). While treatments involving radiation and chemotherapy currently exist, disease must be detected early in order for the treatments to be somewhat effective, and there is no effective treatment after metastasis occurs (2). Additionally, current therapies do not mitigate tumor immunosuppression. Decreasing the tumor-associated immunosuppressive conditions while activating antitumor immunity could prevent recurrence and metastasis, possibly leading to an effective treatment for cancer (3). Tumor cell vaccines could possibly address this issue and have become a …

Modeling The Adaptive Immune Response To Mutation-Generated Antigens, Rory J. Geyer

University Scholar Projects

Somatic mutations may drive tumorigenesis or lead to new, immunogenic epitopes (neoantigens). The immune system is thought to represses neoplastic growths through the recognition of neoantigens presented only by tumor cells. To study mutations as well as the immune response to mutation-generated antigens, we have created a conditional knockin mouse line with a gene encoding, 5’ to 3’, yellow fluorescent protein (YFP), ovalbumin (which is processed to the immunologically recognizable peptide, SIINFEKL), and cyan fluorescent protein (CFP), or, YFP-ovalbumin-CFP. A frame shift mutation has been created at the 5’ end of the ovalbumin gene, hence YFP should always be expressed, …

Modeling The Adaptive Immune Response To Mutation-Generated Antigens, Rory J. Geyer

Honors Scholar Theses

Somatic mutations may drive tumorigenesis or lead to new, immunogenic epitopes (neoantigens). The immune system is thought to represses neoplastic growths through the recognition of neoantigens presented only by tumor cells. To study mutations as well as the immune response to mutation-generated antigens, we have created a conditional knockin mouse line with a gene encoding, 5’ to 3’, yellow fluorescent protein (YFP), ovalbumin (which is processed to the immunologically recognizable peptide, SIINFEKL), and cyan fluorescent protein (CFP), or, YFP-ovalbumin-CFP. A frame shift mutation has been created at the 5’ end of the ovalbumin gene, hence YFP should always be expressed, …

Targeted Sirna Delivery Methods For Rnai-Based Therapies, Di Chen

Electronic Thesis and Dissertation Repository

RNAi has great potential in future therapeutics as it has the ability to regulating many disease-related genes. However, many barriers prevent practical applications. To overcome the barriers, the specific targeting, efficient delivery system, the validated gene and the potent siRNA sequence are all vital important. The studies throughout this thesis have been focued on examining the validation of three RNAi therapies for two different disease models: allergic contact dermatitis and melanoma. For allergic contact dermatitis, I developed and tested a novel topical delivery system for siRNAs targeting TNFα (siTNFα) and MyD88 siRNA (siMyD88). While siRNAs applied without the transdermal enhancer …