Researchers Identify Immune Cells Targeting KSHV in Kaposi Sarcoma Tumors
Researchers analyzing tumor biopsies from 144 Ugandan adults with Kaposi sarcoma identified over 4,000 T-cell receptors with predicted specificity for KSHV- or HIV-encoded peptides, and validated four KSHV-specific TCRs that recognize cells undergoing active viral replication. The study found that KSHV-specific T cells are recruited to tumors rather than remaining detectable primarily in blood, helping explain why prior blood-based studies described weak immune responses to the virus. These findings provide the first characterized public T-cell responses to KSHV and lay groundwork for developing T-cell-based immunotherapies against Kaposi sarcoma and related malignancies.
A preprint study posted to bioRxiv examined T-cell receptor (TCR) repertoires from tumor biopsies of 144 Ugandan adults with Kaposi sarcoma (KS), including 106 people living with HIV and 38 HIV-seronegative individuals. Using computational prediction of MHC-restricted peptide specificity, the researchers identified more than 4,000 beta-chain TCRs putatively targeting KSHV or HIV antigens. Fourteen candidate TCRs were experimentally validated; four KSHV-specific TCRs recognized peptides encoded by lytic viral genes ORF6, ORF57, and ORF59, and were confirmed to respond to KSHV-infected cells undergoing lytic reactivation. Three additional HIV-specific TCRs, found exclusively in tumors from HIV-positive participants, showed high-avidity recognition of HIV Vpr and Nef peptides. Notably, TCRs targeting ORF6 and ORF57 were shared across multiple unrelated individuals, representing the first documented public T-cell responses to KSHV. The authors argue that the tumor microenvironment concentrates KSHV-specific T cells that are too sparse to detect reliably in peripheral blood, reframing the virus's immunological profile. The identification of these TCRs is presented as a foundation for engineering adoptive T-cell therapies for KS, primary effusion lymphoma, and KSHV-associated multicentric Castleman's disease.
What's missing
As a preprint, this study has not yet undergone formal peer review, and the computational MHC-peptide binding predictions underlying TCR identification carry inherent false-positive rates that are not fully quantified. The study population is limited to Ugandan adults, and it is unclear whether the identified public TCR responses generalize to other geographic or demographic populations with different HLA allele distributions. Functional cytotoxicity assays (e.g., killing of KSHV-infected target cells) beyond peptide recognition were not reported, leaving the in vivo effector capacity of these TCRs uncharacterized.
What different sources said
- bioRxivCenter
Cytotoxic T cells targeting lytic KSHV gene products infiltrate Kaposi sarcoma tumors
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