Cytotoxic T cells targeting lytic KSHV gene products infiltrate Kaposi sarcoma tumors

Kaposi sarcoma-associated herpesvirus (KSHV) is the etiologic agent of Kaposi sarcoma (KS), primary effusion lymphoma (PEL), and KSHV-associated multicentric Castleman's disease (MCD), malignancies that predominantly arise in the context of T-cell deficiency. Unlike responses to other human herpesviruses such as EBV and CMV, KSHV-specific T-cell responses detected in blood have been described as heterogeneous and low-intensity. Hypothesizing that KSHV-specific T cells are recruited to KS tumors, we analyzed the T-cell receptor (TCR) repertoire of biopsies from 144 Ugandan adults with KS (106 people living with HIV [PLWH], 38 HIV-seronegative) and identified >4,000 αβ TCRs with predicted specificity for KSHV- or HIV-encoded peptides presented by specific MHC alleles. We tested 14 putative KSHV- or HIV-specific TCRs for recognition of cells presenting cognate peptides in the predicted MHC context. Three novel HIV-specific TCRs, found only in tumors from PLWH, exhibited high-avidity, MHC-restricted recognition of HIV Vpr and Nef peptides previously identified as CD8+ T-cell targets. Four KSHV-specific TCRs, detected in tumors from both PLWH and HIV-seronegative individuals, recognized peptides encoded by the lytic KSHV genes ORF6, ORF57, and ORF59. The ORF6- and ORF57-specific TCRs were observed in multiple individuals and constitute the first examples of public T-cell responses to KSHV. We then confirmed that these four KSHV-specific TCRs recognized KSHV-infected cells undergoing lytic reactivation. Identification of TCRs specific for KSHV lytic gene products will enable the development of T-cell-based therapies for KS and other KSHV-associated diseases.