Cancer Biology Commons^™

Pi3kδ Inhibition Alters Cd8 T Cell Differentiation And Reprograms The Tumor Microenvironment Following Adoptive Immunotherapy, Alexandrea Joy Turnquist

Dartmouth College Ph.D Dissertations

T cell exhaustion remains a significant barrier to effective adoptive cell therapy in solid tumors. Here, we demonstrate that in vitro treatment with the PI3Kδ inhibitor CAL-101 generates T cells with enhanced stemness and metabolic fitness, though the stemness of these cells is not dependent on HIF-1α -dependent mechanisms. These cells show increased mitochondrial dependence and spare respiratory capacity while maintaining normal basal metabolism. Under chronic antigen stimulation, CAL-101-treated T cells, including human T cells, resist terminal exhaustion and maintain stem-like properties. Using single-cell RNA sequencing and spatial transcriptomics of B16 melanoma tumors, we found that CAL-101-treated T cells preferentially …

From Antigen Presentation To Tumor Control: Mechanisms Of Type I Conventional Dendritic Cell-Based Cancer Vaccines, Josue E. Pineda

Dissertations and Theses (Open Access)

Type 1 conventional dendritic cells (cDC1s) are important for generating and sustaining antitumor immunity. Accordingly, the abundance of cDC1s in human tumors correlates with improved outcomes in cancer. Capitalizing on this role, we previously demonstrated that vaccination with in vitro-derived murine cDC1s elicits durable tumor control in multiple preclinical models; however, the immunological mechanisms underlying the efficacy of cDC1 vaccination remain unclear. Here, we examined whether in vitro-derived cDC1s resemble tumor-infiltrating DC populations and whether MHC-I and MHC-II antigen presentation contribute to cDC1-mediated tumor control following vaccination in melanoma.

As expected, MHC-I- or MHC-II-deficiency had minimal impact on …

Understanding Epigenomic Landscapes In Cancer Progression And Immunotherapy Response, Jonathan Schulz

Dissertations and Theses (Open Access)

Nonmutational epigenomic reprogramming has emerged as a key hallmark of cancer that plays crucial roles in tumor evolution during its progression and response to therapy. However, the extent and nature of epigenomic reprogramming remains poorly understood. This dissertation examines how epigenetic regulation shapes cancer progression and response to immunotherapy. Working at the intersection of cancer biology and computational genomics, it develops analytical frameworks for characterizing chromatin structure and DNA methylation across diverse tumor contexts and uses these frameworks to address two complementary biological questions: how promoter-associated chromatin organization varies across cancer types, and how epigenetic perturbation modulates tumor immunogenicity in …

Exploration Of A Relationship Between The Activities Of Trail And 4’-Trifluoromethoxychalcone., Abigail C. Ernst

Undergraduate Theses

Cancer is the overgrowth of dysregulated or mutated cells that affects 1 in 3 Americans. Chalcones are natural products with many possible derivatives, such as 4’-trifluromethoxychalcone (4TF), developed in Dr. Krzysiak’s lab, which exhibit anticancer activity against cancer cell lines. Tumor Necrosis Factor-Related Apoptosis-Inducing Ligand (TRAIL) is a tumor surveillance cytokine that acts on two receptor types: death receptors and decoy receptors. One way cancer cells can become resistant to TRAIL is by upregulating decoy receptors and/or downregulating death receptors. In this study, MTS assays evaluated the potential relationship between TRAIL and 4TF that sensitizes A549 cells to TRAIL. The …

Mitochondrial Transfer And Induced Ros As A Therapeutic Strategy In Idh2-Mutant Chondrosarcoma, Vegas R. Bedder, Caleb Wyckoff, Chris Osgood, Gavin A. Vasquez, Michael Stacey

Knowledge and Creativity Expo

Chondrosarcoma (CS) are common bone cancers that produce cartilaginous tumors and are extremely refractive to chemo-and-radiation therapies, leaving very limited treatment options. They contain mutations in the isocitrate dehydrogenase genes, IDH1 or IDH2. Either IDH1 or IDH2 mutations are present in individual tumors, but not both. They both convert alphaketoglutarate (αKG) into the potent oncometabolite D-2-hydroxyglutarate (D2HG). D2HG can be transported from the tumors to cells of the tumor microenvironment (TME) where it can alter metabolic and epigenetic profiles in recipient cells. The process of α-KG to D2HG conversion occurs in the cytoplasm of IDH1 mutant cells, and in the …

The Role Of Tumor Microenvironment In Glioblastoma Multiforme(Gbm) Therapeutic Resistance, Kwesi E. Taylor

Master's Theses or Doctor of Nursing Practice

Despite significant advances in cancer research and treatment, Glioblastoma multiforme (GBM) remains one of the most difficult cancers to treat effectively, with minimal improvement in long-term survival rates over the past few decades. This is largely attributed to tumor heterogeneity and the ability of tumor cells to develop adaptive resistance mechanisms supported by the tumor microenvironment (TME). Although the TME is recognized as a key contributor to tumor progression and therapeutic resistance, the underlying molecular pathways and regulatory genes remain incompletely understood. This study investigated the role of the tumor microenvironment in GBM therapeutic resistance using a bioinformatics approach. Single-cell …

Comparative Spatial Biology: A Cross-Species Analysis Of Canine Oral Cancers As Models For Human Disease, Ram Pradhyumnan

Honors Undergraduate Theses

Oral squamous cell carcinoma (OSCC), one of the most common malignancies of the oral cavity, remains a clinically challenging disease due to its aggressive behavior, late-stage diagnosis, and limited improvements in therapeutic outcomes over recent decades. A significant barrier to progress in OSCC research and treatment is the lack of suitable preclinical models that recapitulate the complexity and natural progression of the disease. Most current models—including cell lines, xenografts, and genetically engineered mice—fail to capture key features such as the spatial organization of tumor epithelium, interactions with an intact immune system, and the stepwise evolution from normal mucosa to invasive …

Investigating The Immunostimulatory Potential Of Dsrna-Silk Nanoparticle Complexes In Melanoma, Samuel J. Peters

Theses and Dissertations (Comprehensive)

The rate of resistance to immune checkpoint inhibitor treatment in metastatic melanoma is quite high, with an overall rate of 70%. Melanoma achieves these high rates of resistance by suppressing the immune response in the tumour microenvironment (TME), making them immunologically “cold”. The type 1 interferon response could be leveraged to initiate immune responses in melanoma, making their “cold” TMEs “warm” again. Double-stranded ribonucleic acids (dsRNAs) are potent activators of an innate immune response; however, they are susceptible to degradation by nucleases present in the body and need a carrier. Silk nanoparticles (SNPs) are an ideal drug-delivery platform as they …

Ovarian Cancer Immunology And Immunotherapy: Editorial Note, Chris D. Platsoucas

Biological Sciences Faculty Publications

[Introduction] As the guest editor of the Special Issue on Ovarian Cancer Immunology Immunotherapy, I would like to include certain brief comments on the current state of the field and to introduce the Special Issue. Ovarian carcinoma and malignant melanoma are the first human tumors where immune responses, primarily restricted to autologous tumor cells, were first demonstrated. T-cell lines and clones developed in recombinant interleukin-2 (rIL-2) from tumor-infiltrating lymphocytes (TIL) from these tumors exhibited cytotoxicity and/or cytokine production, primarily restricted to autologous tumor cells. The T-cell receptor (TCR) and the CD3 differentiation antigen on effector T cells and HLA on …

Dielectrophoretic Biomarkers For Cancer Detection And Cell Analysis: Integrating Microfluidics And Ai, Raphael Olumide Oladokun

Graduate Theses, Dissertations, and Problem Reports (ETD)

Pancreatic ductal adenocarcinoma (PDAC) carries a five-year survival rate of 13%, driven largely by late-stage diagnosis and the absence of sensitive noninvasive screening tools. Current diagnostic methods lack the sensitivity to detect disease-associated systemic changes at early and precancerous stages, representing a critical clinical gap. This dissertation addresses the central hypothesis that PDAC and its pathological subtypes induce measurable, disease-associated electrophysiological changes in circulating PBMCs that can serve as correlative liquid-biopsy biomarkers. To test this hypothesis, this work asks: can dielectrophoresis (DEP), impedance and zeta potential analysis with AI-assisted classification distinguish benign pancreatic conditions (non-malignant control), precancerous lesions (primarily IPMNs), …

Host-Intrinsic Factors Determine Anti-Tumor Efficacy Of Exercise In Pancreatic Ductal Adenocarcinoma, Sumedha Pareek

Dissertations and Theses (Open Access)

Pancreatic Ductal Adenocarcinoma (PDAC) is the third leading cause of cancer-related deaths with a low 5-year relative survival rate of approximately 13.3% for all stages combined. We have previously shown that exercise can improve quality of life and enhance functional capacity among patients with PDAC. Exercise induces a variety of changes in the tumor microenvironment with beneficial effects in several tumor types. However, our understanding of the clinical effects of exercise and the mechanisms that mediate anti-tumor effects are limited in pancreatic cancer.

In this project, using C57BL/6 mice from Taconic Biosciences (Tac) and Jackson Laboratories (Jax), we established a …

A Cancer Education Needs Assessment: Informing Middle-Aged Female Patients About The Relationships Between Obesity And Women’S Health Concerns In The Reproductive System, Breast, And Endometrial Health, Batul Mirza

MUSC Theses and Dissertations

Obesity significantly impacts women’s health, particularly among middle-aged women, by increasing the risk of hormone-sensitive cancers such as breast, endometrial, and reproductive system cancers. This study examines the educational needs of this demographic group regarding obesity-related cancer risks and explores effective intervention strategies. Obesity-induced mechanisms – hormonal imbalances, chronic inflammation, and insulin resistance – drive cancer susceptibility, emphasizing the need for targeted health education. The study employs a qualitative design, which includes interviews with subject matter experts (SMEs) and surveys of middle-aged women. The goal is to assess awareness, perceived barriers, and preferred learning methods. Findings suggest that with many …

Which Costimulatory Domains In Chimeric Antigen Receptor T Cells Induce Cytokine Responses That Are Linked To A More Toxic Car T Cell Therapy In Acute Lymphocytic Leukemia?, Elisabeth Cohen

Longwood Senior Thesis Proposal

No abstract provided.

Fc Gamma Receptors Facilitate Antigenic Modulation Of Lilrb4 And Function As Predictive Biomarkers In Acute Monocytic Leukemia, Joshua Morse

Dissertations and Theses (Open Access)

Acute monocytic leukemia (monocytic AML) is a subtype of AML marked by a proliferation of abnormal monoblasts. This subtype represents approximately 10% of AML cases. The prognosis of monocytic AML is poor, with a 5-year survival of ~30%. Most patients are diagnosed at an age when they are unlikely to survive first-line non-targeted cytotoxic chemotherapy as a bridge to hematopoietic stem cell transplant (HSCT). Even patients who achieve remission commonly relapse. This population of patients would greatly benefit from precision-targeted therapies but currently there are none approved for monocytic AML.

Leukocyte immunoglobulin-like receptor B4 (LILRB4) is an immune checkpoint expressed …

Impact Of Tumor Cell Expressed Cd38 On Metastasis And Immune Evasion In Breast Cancer, Tanvi Visal

Dissertations and Theses (Open Access)

Triple-negative breast cancer (TNBC) is a highly metastatic breast cancer subtype. The epithelial-to-mesenchymal transition (EMT) of cancer cells is a key feature of the metastatic cascade and is not a binary process but often generates malignant cells with both epithelial (E) and mesenchymal (M) traits known as hybrid EM cells. Recent studies highlight the enhanced metastatic potential of the hybrid EM cells. However, molecular insights and targetable vulnerabilities within hybrid EM remain elusive. We discovered that hybrid EM murine tumors are enriched in CD38, an immunesuppressive molecule associated with worse clinical outcomes in liquid malignancies but relatively understudied in solid …

Harnessing The Immunomodulatory Potential Of Radiofrequency Ablation To Improve Therapeutic Outcomes In Pancreatic Ductal Adenocarcinoma, Bhumi Maniyar

Dissertations and Theses (Open Access)

Pancreatic ductal adenocarcinoma (PDAC) continues to rank among the most lethal cancers with poor prognosis. PDAC is characterized by a thick desmoplastic stroma, severe immunological suppression, and resistance tostandard treatments. The need for innovative therapeutic approaches is highlighted by the tumor microenvironment's (TME) critical role in promoting disease development and reducing the effectiveness oftreatment. A promising locoregional treatment that can induce tumor necrosis and modify the TME is endoscopic ultrasound-guided radiofrequency ablation (EUS-RFA). However, there is still minimal understanding around its wider impact on stromal remodeling and immunological activation. This study investigates the immunomodulatory effects of RFA combined with neoadjuvant …

Exploring The Immunologic Consequences Of Atrx Deficiency In Glioma, Benjamin Whitfield

Dissertations and Theses (Open Access)

ATRX is a key chromatin regulator that is frequently mutated across multiple cancer types. One of the most common ATRX-mutated tumor types is the adult-type glioma, IDH-mutant, Astrocytoma. It is known that ATRX mutation leads to increases in DNA damage, replication stress, and global epigenetic regulation at a cell level; however, less is known about the impact of ATRX mutation on immune signaling. Furthermore, little is known about the interaction of ATRX loss with gain-of-function mutations in IDH. In this paper we set out to explore the impact of ATRX loss on immune signaling in gliomas, both in the context …

Stat3, Nf-Κb, And Estrogen Receptor Beta: The Balance Of Inflammation In K-Ras Mutant Lung Adenocarcinoma, Michael J. Clowers

Dissertations and Theses (Open Access)

K-ras mutant lung adenocarcinoma (KM-LUAD) is a difficult-to-treat cancer subtype in which chronic inflammation pervades the tumor immune microenvironment (TIME). Pro-inflammatory pathways dampen the response to treatments, including immune checkpoint inhibitors, necessitating therapies that target this inflammatory signaling network in the TIME. This network is underpinned by interaction and coordination of two inflammatory pathways: signal transducer and activator of transcription 3 (STAT3) and nuclear factor kappa B (NF-κB). The balance of these transcription factors determines the degree of anti- vs. pro-tumor immunity, and a skewing towards STAT3 is known to promote tumor development and a pro-tumor TIME. It is also …

Investigating The Ability Of Foxo1 To Maintain Stem Cells, Stella A. Rios, Megan E. Keniry

Research Symposium

Background: Our group discovered that FOXO transcription factors drive stem gene expression in cancer to promote aggressiveness. Work by our group and others demonstrated that FOXO factors universally maintain stem cells including in cancer, embryonic, hematogenic and neuronal contents. Our current efforts are delineating the molecular underpinnings by which FOXO factors halt differentiation to maintain stem cells.

In this project, we are employing myoblasts as a valuable model to examine how Foxo1 maintains stem cells. Foxo1-regulated genes in myoblasts closely parallel its targets in glioblastoma and basal breast cancer stem cells, including targets such as Leukemia Inhibitory Factor, …

Physical Ablative Methods And Cancer Cell Death: Implications For Immunity And Therapies, Alessandra Rossi, Claudia Muratori

Bioelectrics Publications

Surgery has traditionally been a cornerstone in cancer treatment, yet its feasibility can be limited by factors such as tumor location and patient health conditions. When surgery is not viable, thermal and pulsed electric field (PEF)-based ablation technologies offer valuable alternatives. Emerging evidence suggests that these approaches not only target tumors effectively but also stimulate antitumor immune responses. In this review, we begin by examining the distinctive features of hyperthermic treatments (radiofrequency and microwave ablation), cryoablation, and PEF-technologies. Subsequently, we discuss the mechanisms of cell death, stress responses, and release of danger signals triggered by these diverse ablation technologies. Finally, …

Timigp: A Computational Framework To Determine The Tumor Immune Microenvironment Associated With Prognosis And Immunotherapy Response, Chenyang Li

Dissertations and Theses (Open Access)

Accumulating evidence has suggested that the tumor immune microenvironment (TIME) drastically impacts cancer patients’ clinical outcomes, including prognosis and immunotherapy response. However, understanding TIME remains challenging due to its complexity and heterogeneity. In this dissertation, we introduce TimiGP (Tumor Immune Microenvironment Illustration based on Gene Pairs), a computational framework designed to address this challenge. Leveraging single-cell RNA-seq (scRNA-seq) and bulk gene expression data alongside clinical information, TimiGP constructs a cell-cell interaction network that elucidates the relationship between immune cell function and relevant clinical outcomes, such as prognosis and treatment response. With immunological insights, these cell-cell interactions also facilitate the development …

The Role Of Ganglioside Gd2 And Gd3 Synthase (St8sia1) In The Regulation Of Immune Suppression In Breast Cancer, Bolutyfe Oderinde

Dissertations and Theses (Open Access)

Gangliosides are acidic glycosphingolipids involved in cell adhesion, proliferation, and modulation of signal transduction pathways. It has been reported that tumor-shed gangliosides influence the activity of immune cells including macrophages, NK cells, and T cells. GD3 synthase (GD3S) is the key enzyme that regulates the biosynthesis of the b and c series gangliosides, particularly GD3 and GD2, and studies have shown that GD3S is upregulated in most tumors and plays a role in tumor progression. Similarly, we have previously found GD3S to be significantly upregulated in GD2+ breast cancer stem cells (BCSC) compared to GD2- cells, and the knockdown of …

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 …

Dying Right: Supporting Anti-Cancer Therapy Through Immunogenic Cell Death, Elizabeth Schmitz

Theses & Dissertations

The primary goal of most anti-cancer therapy is to eradicate neoplastic cells. Simultaneously, neoplastic cell death is the first step of the cancer-immunity cycle, which starts with the release of antigens from cancer cells and ends with T-cell directed killing of cancer cells, in addition to long-standing memory to tumor antigens encountered. Immunogenic damage-associated-molecular patterns (DAMPs) are endogenous cell molecules repurposed in times of insurmountable cell stress (e.g., CALR, ATP, HMGB1) to facilitate communication between dying cells and adaptive immune cells, acting as adjuvants for the cancer-immunity cycle, in a cellular fate termed immunogenic cell death (ICD). It …

Optimizing Immunotherapies For Improved Cancer Treatment, Anne Talkington, Anthony Kearsley

Biology and Medicine Through Mathematics Conference

No abstract provided.

Mucins: Drivers Of Cancer Cell And Microenvironment Crosstalk In Pancreatic Cancer, Xiaoqi Li

Theses & Dissertations

Mucins facilitate the pancreatic cancer (PC) initiation, progression, and metastasis. Among mucins, MUC4 has been reported to inhibit lymphokine-activated cell killing and induce the apoptosis of cytotoxic T-cells. Counterintuitively, MUC4 expression is upregulated by multiple T-cell-secreted cytokines, such as IFN-γ, IL-17, and stroma-secreted factors like retinoic acid. Previously, we have identified that nuclear receptor coactivator 3 (NCOA3) regulates the MUC1 and MUC4 expression by increasing chromatin accessibility and maintaining protein stability. However, the comprehensive crosstalk mediated by MUC4 in cancer cells and T-cells and how its upstream regulator, NCOA3, modifies the cancer cell-intrinsic behavior is still elusive. Here, we show …

Therapeutic Effects Of Bet Protein Inhibition In B-Cell Malignancies And Beyond, Audrey L. Smith

Theses & Dissertations

Chronic lymphocytic leukemia (CLL) develops through a combination of intrinsic genetic defects, constitutively active survival/proliferation signaling pathways, and complex microenvironment interactions. Redundant tumor microenvironment (TME) immuno-suppressive mechanisms and epigenetic maintenance of terminal T-cell dysfunction also greatly hinder anti-tumor T-cell responses in CLL. Small-molecule agents targeting the B-cell receptor (BCR) pathway and anti-apoptotic proteins alone or in combination with chemo-immunotherapy have revolutionized the management of CLL, yet there is still a significant need for novel therapeutic strategies to yield durable tumor elimination. Bromodomain and extra-terminal domain (BET) proteins are epigenetic readers that bind to acetyl-lysine residues on histones to regulate gene …

Oxidative Phosphorylation In Melanoma Brain Metastases: A Regulator Of The Tumor Immune Landscape, Renato A. Guerrieri

Dissertations and Theses (Open Access)

Previously, we demonstrated via RNA-sequencing analysis of murine intracranial melanoma tumors that pharmacologic inhibition of oxidative phosphorylation (OXPHOS) results in increased expression of genes consistent with activated anti-tumor immune responses. The central hypothesis of this dissertation is that OXPHOS plays a critical role in the pathogenesis and immune regulation of melanoma brain metastases (MBMs).

The functional significance of OXPHOS was assessed through genetic inhibition, involving knockout (KO) of key regulatory genes such as Ppargc1a (PGC1a) and Ndfus4 (NDUFS4), a component of mitochondrial complex I. PGC1a KO in an RCAS-TVA mouse model of autochthonous lung and brain tumors developing from primary …

Mast Cells In Mammary Carcinoma, Alexandria M. Ashbaugh

Undergraduate Honors Theses

Breast cancer (BC) is an aggressive disease that takes the lives of thousands of women every year. Although knowledge and treatment of this disease have improved over the years, much is still to be discovered about BC. One area of expertise that we are currently trying to learn more information about is the mast cell (MC) and its role in BC growth and development. The MC is an immune system component discovered in tumors' extracellular matrix (ECM). As a tumor grows within body tissues, the tumor recruits the MC from surrounding connective tissues to the tumor, using signaling cytokines such …

Loss Of Ptdss1 In Tumor Cells Improves Anti-Pd-1 Therapy, Jielin Liu

Dissertations and Theses (Open Access)

PTDSS1 (Phosphatidylserine synthase 1) encodes an enzyme that facilitates production of phosphatidylserine (PS), which mediates a global immunosuppressive signal. Here, based on in vivo CRISPR screen, we identified PTDSS1 as a target to improve anti-PD-1 therapy. Depletion of PTDSS1 in tumor cells increased expression of IFNγ-regulated genes, including B2m, Cxcl9, Cxcl10, and Stat1. Loss of PTDSS1 in tumor cells also led to increased expression of MHC-I, which was associated with increased expression of cytolytic function related genes in CD8⁺ T cells and increased frequency of an iNOS⁺ myeloid subset. A gene signature derived from the iNOS⁺ myeloid …