Dataset Information

Immunophenotypic analysis in participants with Kaposi sarcoma following pomalidomide administration.

ABSTRACT:

Objective

The aim of this study was to evaluate baseline differences by HIV status and the impact of pomalidomide on lymphocyte counts and T-cell subsets in patients with Kaposi sarcoma.

Design

We prospectively evaluated CD4 + and CD8 + T-cell phenotypes in 19 participants with Kaposi sarcoma enrolled on a phase 1/2 study of pomalidomide (NCT01495598), seven without HIV and 12 with HIV on antiretroviral therapy.

Methods

Trial participants received pomalidomide 5 mg orally for 21 days of 28-day cycles for up to 1 year. Flow cytometry was performed on peripheral blood mononuclear cells at baseline, after three cycles, and at end-of-treatment. Lymphocyte count and T-cell subset comparisons were evaluated by Wilcoxon signed-rank and Mann--Whitney tests.

Results

At baseline, HIV + participants had lower CD4 + cell counts (median 416 vs. 742 CD4 + T cells/μl, P = 0.006), and a decreased proportion of CD57 + (senescent) CD8 + T cells ( P = 0.007) compared with HIV - participants. After three cycles, pomalidomide led to an increased proportion of CD45RO + CD27 + (central memory) CD4 + ( P = 0.002) and CD8 + ( P = 0.002) T cells, a decrease in CD45RO - CD27 - (effector) CD4 + cells ( P = 0.0002), and expansion of CD38 + /HLADR + (activated) CD4 + ( P = 0.002) and CD8 + ( P ≤ 0.0001) T cells. Increased numbers of activated CD8 + T cells persisted at end-of-treatment ( P = 0.002). After three cycles and at end-of-treatment, there was reduction in the proportion of CD57 + (senescent) CD4 + ( P = 0.001, 0.0006), and CD8 + ( P = < 0.0001, 0.0004) T cells.

Conclusion

Administration of pomalidomide decreased T-cell senescence and increased T-cell activation in patients with Kaposi sarcoma, suggesting pomalidomide activity in Kaposi sarcoma stems in part from its immunomodulatory effects.

SUBMITTER: Lurain K

PROVIDER: S-EPMC10527758 | biostudies-literature | 2023 Sep

REPOSITORIES: biostudies-literature

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Publications

Immunophenotypic analysis in participants with Kaposi sarcoma following pomalidomide administration.

Lurain Kathryn K Polizzotto Mark N MN Krug Laurie T LT Shoemaker Griffin G Singh Amrit A Jensen Stig M R SMR Wyvill Kathleen M KM Ramaswami Ramya R Uldrick Thomas S TS Yarchoan Robert R Sereti Irini I

AIDS (London, England) 20230619 11

<h4>Objective</h4>The aim of this study was to evaluate baseline differences by HIV status and the impact of pomalidomide on lymphocyte counts and T-cell subsets in patients with Kaposi sarcoma.<h4>Design</h4>We prospectively evaluated CD4 + and CD8 + T-cell phenotypes in 19 participants with Kaposi sarcoma enrolled on a phase 1/2 study of pomalidomide (NCT01495598), seven without HIV and 12 with HIV on antiretroviral therapy.<h4>Methods</h4>Trial participants received pomalidomide 5 mg orally f ...[more]

PMID: 37352498

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Project description:Intra-host tumor virus variants may influence the pathogenesis and treatment responses of some virally-associated cancers. However, the intra-host variability of Kaposi sarcoma-associated herpesvirus (KSHV), the etiologic agent of Kaposi sarcoma (KS), has to date been explored with sequencing technologies that possibly introduce more errors than that which occurs in the viral population, and these studies have only studied variable regions. Here, full-length KSHV genomes in tumors and/or oral swabs from 9 Ugandan adults with HIV-associated KS were characterized. Furthermore, we used deep, short-read sequencing using duplex unique molecular identifiers (dUMI)-random double-stranded oligonucleotides that barcode individual DNA molecules before library amplification. This allowed suppression of PCR and sequencing errors to ~10-9/base as well as afforded accurate determination of KSHV genome numbers sequenced in each sample. KSHV genomes were assembled de novo, and rearrangements observed were confirmed by PCR and Sanger sequencing. 131-kb KSHV genome sequences, excluding major repeat regions, were successfully obtained from 23 clinical specimens, averaging 2.3x104 reads/base. Strikingly, KSHV genomes were virtually identical within individuals at the point mutational level. The intra-host heterogeneity that was observed was confined to tumor-associated KSHV mutations and genome rearrangements, all impacting protein-coding sequences. Although it is unclear whether these changes were important to tumorigenesis or occurred as a result of genomic instability in tumors, similar changes were observed across individuals. These included inactivation of the K8.1 gene in tumors of 3 individuals and retention of a region around the first major internal repeat (IR1) in all instances of genomic deletions and rearrangements. Notably, the same breakpoint junctions were found in distinct tumors within single individuals, suggesting metastatic spread of rearranged KSHV genomes. These findings define KSHV intra-host heterogeneity in vivo with greater precision than has been possible in the past and suggest the possibility that aberrant KSHV genomes may contribute to aspects of KS tumorigenesis. Furthermore, study of KSHV with use of dUMI provides a proof of concept for utilizing this technique for detailed study of other virus populations in vivo.

Dataset Information

Immunophenotypic analysis in participants with Kaposi sarcoma following pomalidomide administration.

Objective

Design

Methods

Results

Conclusion

Publications

Immunophenotypic analysis in participants with Kaposi sarcoma following pomalidomide administration.

Similar Datasets

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