Identifying Neoantigens in TENT5C Frameshift Alleles for mRNA Cancer Vaccine Design Personalized to Primary Effusion Lymphomas (PEL) Caused by Kaposi Sarcoma Herpesvirus (KSHV)

Abstract:

Kaposi sarcoma herpesvirus (KSHV), also known as human herpesvirus-8 (HHV-8), is a non-integrating oncovirus that causes a wide spectrum of malignancies or disorders, including Castleman Disease (CD), Kaposi Sarcoma (KS), and Primary Effusion Lymphoma (PEL). In the latter case, KSHV is a major driver of PEL which represents a malignancy of the B-cell lineage. Under normal conditions, mature but naïve B-cells that become challenged by antigen are granted mitotic rights by follicular helper T (T_F_H) or T_h2 cells during immunological synapse formation, typically at paracortical / cortical boundaries in lymph nodes. Mitotic daughters of activated B-cells differentiate into plasmablasts before becoming post-mitotic plasma cells capable of extensive antibody production. KSHV-infected B-cells that differentiate into plasmablasts resist terminal differentiation, retaining mitotic activities. PEL patients exhibit extensive plasmoblast numbers that accumulate within the bodily cavities (i.e., pleural, pericardial, or peritoneal) replete with fluids (i.e., effusions). PEL tumors are rarely solid but rather distributed across effusions. As a KSHV-driven cancer, PEL afflicts the immunosuppressed (i.e., organ transplantations) and immunocompromised (i.e., HIV/AIDS). There is currently no available vaccine targeting the KSHV agent of PEL. We datamined open-access portals including The Cancer Genome Atlas (TCGA) for PEL-enriched cancer cases harboring frameshift alleles. Roughly half of the frameshift alleles map to the TENT5C gene which encodes a terminal nucleotidyltransferase. The TENT5C enzyme functions as a cytosolic poly(A) polymerase, extending the lifespans of messages that are key for B-cell activities, including heavy chain and light chain mRNA molecules. A tempting hypothesis is TENT5C might extend pro-survival, anti-apoptotic messages within KSHV-infected plasmoblasts. Cursory analysis reveals that all the TENT5C indel alleles that result in frameshifts are randomly distributed across the gene without mutational hotspots. Nonetheless, elevated rates of TENT5C mutant alleles in PEL cases provides a unique opportunity to hunt for neoantigens that form the basis of cancer mRNA vaccine designs that leverage cytotoxic T lymphocytes that target KSHV-infected PEL.