Suppression of high mobility group box 1 in B16F10 tumor does not inhibit the induction of neoantigen‐specific T cells

Abstract

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.

Alarmins in cutaneous malignant melanoma: An updated overview of emerging evidence on their pathogenetic, diagnostic, prognostic, and therapeutic role

“…Furthermore the potential of this alarmin as a prognostic marker and predictor of therapeutic response has been highlighted as well as its pioneering use as a target for the development of biological and miRNAs‐based drugs 79 . Also supporting the above‐mentioned new therapeutic horizons, is the most recent evidence for the influence of HMGB1 suppression on the induction of neoantigen‐specific T cell immunity 80 . Among the high‐mobility chromosomal proteins, worthy of mention as an alarmin in melanoma is HMGN1.…”

“…79 Also supporting the above-mentioned new therapeutic horizons, is the most recent evidence for the influence of HMGB1 suppression on the induction of neoantigen-specific T cell immunity. 80 Among the high-mobility chromosomal proteins, worthy of mention as an alarmin in melanoma is HMGN1. In the wake of the previously emphasized role of HMGN1 in promoting anti-tumor immunity with a preferential Th1-polarizing ability, only in the past year have there been the first experimental results regarding the design of an HMGN1-based vaccine as part of a combinational immunotherapy, proven effective in eradicating 60%-80% of three different melanin-producing mouse melanomas.…”