Accumulated clinical data of immune checkpoint blockades have suggested the importance of neoantigens in cancer immunity. Tumor antigens are released from dead cancer cells together with cellular components, such as damage-associated molecular patterns (DAMPs), into the tumor microenvironment. We recently reported that high mobility group box 1 (HMGB1), a representative DAMP molecule, showed a negative impact on anti-tumor immunity. However, a positive role of HMGB1 in the initiation of innate and subsequent adaptive immunity has also been demonstrated; thus, the effects of HMGB1 on anti-tumor immunity have not been well understood. In this study, we identified nine immunogenic neoantigen epitopes of B16F10 murine melanoma cells and subsequently investigated the effects of suppression of HMGB1 on the induction of neoantigen-specific immunity using HMGB1-knockout tumors. Neoantigen-reactive T cells were expanded in B16F10 tumor-bearing mice, and T cell receptor repertoire analysis suggested that neoantigen-reactive T cells were oligo-clonally increased in B16F10 tumor bearers. An increase of neoantigen-reactive T cells and oligoclonal expansion of the T cells were similarly detected in HMGB1-knockout tumor-bearing mice. The induction of neoantigen-specific immunity under the suppression of HMGB1 in the tumor microenvironment shown in this study supports further development of combination therapy of HMGB1 suppression with neoantigen-targeted cancer immunotherapies, including immune checkpoint blockade therapy.
Keywords: HMGB1; alarmin; cytotoxic T-lymphocytes; neoantigen; tumor microenvironment.
© 2022 The Authors. Cancer Science published by John Wiley & Sons Australia, Ltd on behalf of Japanese Cancer Association.