Human Endogenous Retrovirus Type K (Herv-K) Env Protein As A Vaccine Target For Herv-K Plus Cancer Prevention

Some tumors, including BC tumors, are poorly responsive or develop resistance to therapy, which creates an impetus to identify novel strategies that potentiate immunotherapy in unresponsive cancers. Vaccines against human BC have shown only limited success for prevention of BC, with the exception of yellow fever vaccine 17D (YFV), which is closely homologous to HERV-K. In order to check immune response in animal models, murine mammary tumor cells (4T1) or melanoma cells (B16F10) were employed to express a full-length HERV-K Env protein obtained from a BC patient with invasive ductal carcinoma (IDC) by stably transfecting with pLVXKenv [full-length HERV-K env, expressing extracellular surface (SU) and transmembrane (TM) domains] or pLVX vector (control). To determine whether the SU or TM has cancer-preventive effects when dosed as an HERV-K antigen vaccine, C57BL/6 female mice were immunized with cyclic dinucleotides (CDN:15 µg) and HERV-K SU (KSU), TM [harboring the HERV-K immunosuppressive domain (ISD)], or GST protein (25 µg) on day 1 and boosted on days 14 and 28. Mice were challenged with B16F10pLVX or B16F10pLVXKenv (3 X 10 5 cells) 18 days after the last boost of immunization. The effect of tumor challenge on tumor growth and weight was compared. Increased weight of pLVXKenv relative to pLVX control cells was observed in mice immunized with GST (2-fold increased weight). In contrast, we observed reduced weight of pLVXKenv relative to pLVX tumors in mice immunized with KSU (50% reduced weight), showing the protective effect of KSU vaccination. This protective effect disappeared in mice immunized with the TM (1.65-fold increased tumor weight), indicating that the ISD of TM may prevent an immune response to the vaccine. Increased anti-HERV-K antibody titers were demonstrated in mice immunized with KSU than with KTM. Significantly increased anti-KSU antibody titers were demonstrated in mice immunized with KSU than with GST. Interestingly, significantly increased anti-KTM antibody titers were demonstrated in mice inoculated with pLVXKenv than with pLVX. Lower percentages of CD3+CD4+, CD3+CD8+, and CD3-NK T cells from tumor tissues were observed in mice immunized with TM or SU protein and challenged with B16F10Kenv cells. Significantly increased proliferation of CD4 or CD8 T cells was demonstrated in mice immunized with KSU protein and challenged with B16F10Kenv cells than after challenge with B16F10pLVX cells. In contrast, significantly decreased proliferation of CD4 and CD8 T cells was demonstrated in mice immunized with TM and challenged with B16F10Kenv cells than with B16F10pLVX cells, reflecting immunosuppression induced by the TM vaccine. In conclusion, HERV-K SU protein, but not TM protein, can be used for cancer prevention and immunotherapy for HERV-K positive cancers. Also, TM blockade may reduce immunosuppression. Citation Format: Feng Wang-Johanning, Jia Li, Ming Li, Gary L. Johanning, Albert Lee, Tianhe Huang. Human endogenous retrovirus type K (HERV-K) env protein as a vaccine target for HERV-K+ cancer prevention [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 1257.