Biology subjects

Coffey, D. G.

Publications and source records attributed to Coffey, D. G..

3 recordsLinked to original sources

bioRxiv2024

The signature of a T-cell response to KSHV persists across space and time in individuals with epidemic and endemic KS from Uganda

Kaposi sarcoma-associated herpesvirus (KSHV) is the etiologic agent of Kaposi sarcoma (KS), which causes significant morbidity and mortality worldwide, particularly in people living with HIV (PLWH) and in sub-Saharan Africa where KSHV seroprevalence is high. Postulating that T-cells specific for KSHV and HIV would be attracted to KS tumors, we performed transcriptional profiling and T-cell receptor (TCR) repertoire analysis of tumor biopsies from 144 Ugandan adults with KS, 106 of whom were also living with HIV. We show that CD8+ T-cells and M2-polarized macrophages are the most common immune cells in KS tumors. The TCR repertoire of T-cells associated with KS tumors is shared across spatially and temporally distinct tumors from the same individual. Clusters of T-cells with predicted shared specificity for uncharacterized antigens, potentially encoded by KSHV or HIV, comprise [~]25% of the T-cells in KS tumors. Single-cell RNA-sequencing of blood from a subset of 9 adults captured 4,283 unique {beta} TCRs carried in 14,698 putative KSHV- or HIV-specific T-cells, which carried an antigen-experienced effector phenotype. T-cells engineered to express a representative sample of these TCRs showed high-avidity recognition of KSHV- or HIV-encoded antigens. These results suggest that a polyspecific, high-avidity KSHV- and HIV-specific T-cell response, potentially inhibited by M2 macrophages, migrates to and localizes with KS tumors. Further analysis of KSHV- and HIV-specific T-cells in KS tumors will provide insight into the pathogenesis of KS and could guide the development of specific immune therapy based on adoptive transfer or vaccination. Author SummaryIn this work, we set out to examine Kaposi Sarcoma (KS) tumor tissue, as well as peripheral blood cells from individuals with KS, both living with and without HIV. Our goal was to identify T-cells that specifically recognize antigens encoded by Kaposi sarcoma-associated herpesvirus (KSHV) or HIV. By analyzing the T-cell repertoire in KS tumor biopsies from people in Uganda with different types of KS, we uncovered clusters of T-cells with previously unknown ability to recognize these viruses. Through single-cell sequencing of peripheral blood cells, we also observed that many of these T-cells had cell-killing properties. Notably, they often coexisted with a subset of macrophages with immunosuppressive properties, which we suspect may be suppressing the function of virus-targeting T-cells. Our findings suggest that additional studies of these virus-targeting T-cells and their interaction with immunosuppressive macrophages could significantly advance the development of effective therapeutics against KS.

immunology↗

bioRxiv2023

The Vk*MYC Mouse Model recapitulates human multiple myeloma evolution and genomic diversity

Despite advancements in profiling multiple myeloma (MM) and its precursor conditions, there is limited information on mechanisms underlying disease progression. Clincal efforts designed to deconvolute such mechanisms are challenged by the long lead time between monoclonal gammopathy and its transformation to MM. MM mouse models represent an opportunity to overcome this temporal limitation. Here, we profile the genomic landscape of 118 genetically engineered Vk*MYC MM and reveal that it recapitulates the genomic heterogenenity and life history of human MM. We observed recurrent copy number alterations, structural variations, chromothripsis, driver mutations, APOBEC mutational activity, and a progressive decrease in immunoglobulin transcription that inversely correlates with proliferation. Moreover, we identified frequent insertional mutagenesis by endogenous retro-elements as a murine specific mechanism to activate NF-kB and IL6 signaling pathways shared with human MM. Despite the increased genomic complexity associated with progression, advanced tumors remain dependent on MYC expression, that drives the progression of monoclonal gammopathy to MM.

cancer biology↗

bioRxiv2022

Chemotherapy Signatures Map Evolution of Therapy-Related Myeloid Neoplasms

Patients treated with cytotoxic therapies, including autologous stem cell transplantation, are at risk for developing therapy-related myeloid neoplasms1, 2. Pre-leukemic clones (i.e., clonal hematopoiesis) are detectable years before the development of these aggressive malignancies3-5, though the genomic events leading to transformation and expansion are not well-defined. Here, leveraging distinctive chemotherapy-associated mutational signatures6-12 from whole-genome sequencing data and targeted sequencing of pre-chemotherapy samples, we reconstruct the evolutionary life-history of 39 therapy-related myeloid malignancies. A dichotomy is revealed, in which neoplasms with evidence of chemotherapy-induced mutagenesis from platinum and melphalan are relatively hypermutated and enriched for complex structural variants (i.e., chromothripsis), while neoplasms with alternative exposures bear a similar profile to de novo acute myeloid leukemia. Using chemotherapy-associated mutational signatures as a temporal barcode in each patients life, we estimate that several complex events and genomic drivers are acquired after chemotherapy exposure. In the case of treatment with high-dose melphalan and autologous stem cell transplantation, we demonstrate that the procedure allows clonal hematopoiesis to escape chemotherapy exposure entirely, and to be reinfused to expand to malignancy. This information reveals a novel mode of malignant progression for therapy-related malignancies that is not reliant on direct mutagenesis or even exposure to chemotherapy, itself, and prompts further investigation into leukemia-permissive effects of cytotoxic drugs.

cancer biology↗