Humanized HLA-DQ8αβ transgenic mice treated with SEG/SEI superantigens exhibit long-term CD4+-mediated anti-tumor responses.

Abstract

Abstract SEG and SEI are primordial S. aureus superantigens (SAgs) notably unaccompanied by human neutralizing antibodies that have hampered the use of classic SAgs as cancer therapeutics. Here we show SEG/SEI presented from a HLA-DQ8αβ (HLA-DQA*0301 and HLA-DQB*0302) tg platform outperform C57BL/6 mice in achieving long term survival in vaccinated and established Lewis lung carcinoma (LLC) and B16-F10 melanoma. Vaccination of DQ8 tg mice with LLC or B16-F10 melanoma followed by SEG/SEI immunization and subsequent tumor challenge resulted in 100% and 83% survival for >150 days respectively, compared to a median survival of 14 days in unvaccinated DQ8 tg controls (p<0.001). Likewise, SEG/SEI treatment of established melanoma in DQ8 tg mice resulted in 100% survival for 70 days compared to a median survival of 20 days in untreated DQ8 tg controls. Similar vaccinations/challenges in C57BL/6 mice produced a median survival of 23–28 days. SEG/SEI-activated splenocytes from DQ8 tg mice displayed a TH-1/TH-17 cytokine phenotype with a threefold greater T cell proliferative and CD4+-mediated cytotoxicity responses, compared to C57BL/6 mice. These surprising data delineate a clear pathway to translation of an SEG/SEI-HLA-DQ8αβ tg platform for melanoma/lung cancer prophylaxis and treatment.