109 research outputs found
Decoding the B cell receptor in endemic Burkitt Lymphoma: Insights into pathogenesis and implications for disease detection
No full textThesis (Ph.D.)--University of Washington, 2017-09The African endemic form of Burkitt Lymphoma (BL) is one of the most common pediatric malignancies in sub-Saharan Africa. BL is particularly prevalent in certain geographic regions, likely due to both environmental and genetic influences. BL is a malignancy of antigen-experienced, germinal center centroblasts. Normal B cells express a functional B cell receptor on their surface that is generated from ordered chromosomal rearrangements at the immunoglobulin (Ig) loci. We performed high-throughput sequencing on genomic DNA extracted from primary BL tumors. The sequencing was focused on the Ig loci from three independent BL patient cohorts to assess the complete repertoire of Ig rearrangements contained in BL tumors. This analysis demonstrated that 55 of 69 tumors harbored a clonal Ig heavy chain (IGH) repertoire. Amongst clonal tumors, a second rearranged IGH allele was only detected in 11 cases, suggesting widespread monoallelic IGH rearrangements in BL tumors. Most tumors were characterized by extensive Ig sequence variation; hundreds of related, but unique, nucleotide sequences were detected in most tumors. These sequence families were associated with both complete VDJ rearrangements and incomplete DJ rearrangements, demonstrating the activity of active mutational processes at the Ig loci in BL tumors. IGH sequences are highly specific and can serve as a molecular barcode for each B cell. Assessment of matched patient blood samples demonstrated that tumor-associated IGH sequences were regularly detected in circulation at diagnosis. Positive detection of circulating tumor DNA at diagnosis was associated with inferior patient survival than when tumor DNA was not detected, suggesting that tumor-specific IGH sequences may have prognostic value for BL patients. The data presented in this dissertation suggest an alternative model of BL pathogenesis and assess the utility of IGH sequences as a biomarker for BL detection. The goal of this work is to expand the BL research repertoire to provide insights that will contribute to disease prevention efforts and ultimately improve the outcome for BL patients
Cellular and Molecular Dissection of the CD8+ T-Cell Response to Kaposi Sarcoma: Implications for Immunotherapeutic Strategies
No full textThesis (Ph.D.)--University of Washington, 2025Kaposi sarcoma-associated herpesvirus (KSHV) is one of two known tumorigenic human herpesviruses and the etiologic agent of Kaposi sarcoma (KS), primary effusion lymphoma (PEL), and multicentric Castleman disease (MCD), malignancies that predominantly arise in the context of T-cell deficiency or dysfunction. There are no approved vaccines, antiviral drugs, or immunotherapies that can prevent or eliminate KSHV infection. The impact of this therapeutic gap is most pronounced in sub-Saharan Africa (SSA), where the burden of KS morbidity and mortality is highest, KSHV is endemic, and HIV-1, the greatest risk factor for KS, is highly prevalent. All other human herpesviruses elicit potent and durable antiviral T-cell responses to control infection. However, studies of circulating T-cell responses to KSHV in the blood suggest that this response is heterogeneous, infrequent, and low-intensity, with the identity of their peptide-MHC targets poorly defined. Given the consistent expression of KSHV in KS tumors, we hypothesized that KSHV-specific T cells would be frequently recruited to KS tumors. We therefore analyzed the TCR repertoire of tumor biopsies from 144 Ugandan adults with KS, 106 of whom were people living with HIV (PLWH). Clusters of T cells with predicted shared specificity for uncharacterized antigens comprised approximately 25% of the T-cell repertoire in the KS tumor microenvironment, representing 4,283 unique αβ TCRs potentially recognizing KSHV- or HIV-encoded peptide antigens. From 25 reconstructed TCRs, we identified two ORF6-specific, HLA-B*45:01-restricted TCRs, one HLA-B*57:03-restricted TCR with specificity for ORF59, and one HLA-A*66:01-restricted TCR recognizing ORF57. The ORF6- and ORF59-specific TCRs were detected in 27-29 and 30 tumors from 14 HLA-B*45:01+ and 10 HLA-B*57:03+ individuals, respectively. Therefore, these TCRs provide the first evidence of a shared, i.e., “public,” T-cell response to KSHV. Primary CD8+ T cells engineered with KSHV-specific TCRs from KS tumor-infiltrating lymphocytes displayed high-avidity, MHC-restricted recognition of two distinct cell types infected with KSHV, B cells (PEL) and endothelial cells (iTIME.219). In parallel, we characterized three novel HIV-specific TCRs within KS tumors from PLWH, two targeting Nef71-79 and one recognizing Vpr34-42, and confirmed the presence of a previously described public HIV-specific TCR recognizing Pol982-990. HIV-specific T cells remained detectable in KS tumors from individuals who had been on antiretroviral therapy for up to five months. Together, these findings demonstrate that KS tumors recruit polyclonal, high-avidity CD8+ T cells recognizing multiple lytic KSHV and in PLWH, HIV antigens. The identification of CD8+ T cells capable of killing diverse KSHV-infected cell types will provide the foundation for rational vaccine design and TCR-based immunotherapeutic strategies to prevent or treat KS
Graft versus Leukemia Reactivity after Allogeneic Stem Cell Transplantation
No full textImmunobiology of allogeneic stem cell transplantation and immunotherapy of hematological disease
Mechanisms of immune evasion and current status of checkpoint inhibitors in non‐small cell lung cancer
No full textIn the past several years, immunotherapy has emerged as a viable treatment option for patients with advanced non‐small cell lung cancer (NSCLC) without actionable driver mutations that have progressed on standard chemotherapy. We are also beginning to understand the methods of immune evasion employed by NSCLC which likely contribute to the 20% response rate to immunotherapy. It is also yet unclear what tumor or patient factors predict response to immunotherapy. The objectives of this review are (1) review the immunogenicity of NSCLC (2) describe the mechanisms of immune evasion (3) summarize efforts to target the anti‐program death‐1 (PD‐1) and anti‐program death‐ligand 1(PD‐L1) pathway (4) outline determinants of response to PD‐1/PD‐L1 therapy and (5) discuss potential future areas for research.Immune checkpoint inhibitors have become an important class of drugs to treat advanced non‐small cell lung cancer (NSCLC), but only about 20% of patients respond to treatment. We discuss the mechanisms of immune evasion employed by NSCLC and potential molecular predictors of response to checkpoint inhibition.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/134103/1/cam4819.pdfhttp://deepblue.lib.umich.edu/bitstream/2027.42/134103/2/cam4819_am.pd
Adoptive Transfer of Allogeneic Antigen-Specific T Cells
No full textAbstractAnimal models and human studies of allogeneic hematopoietic cell transplantation (HCT) demonstrate that immunologic nonidentity between donor and recipient is responsible for a graft versus leukemia (GVL) effect that contributes to complete tumor eradication. A variety of immune cells have been implicated in the GVL effect including NK cells, B cells, and CD4+ and CD8+ T cells that recognize minor histocompatibility (H) or leukemia-associated antigens. Here we discuss strategies for employing T cells specific for minor H antigens to augment the GVL effect
Cytotoxic T-Lymphocyte–Defined Human Minor Histocompatibility Antigens With a Restricted Tissue Distribution
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