Knockdown of High Mobility Group Box 1 in Tumor Cells Attenuates Their Ability to Induce Regulatory T Cells and Uncovers Naturally Acquired CD8 T Cell-dependent Antitumor Immunity

摘要

Although high mobility group box 1 (HMGB1) in tumor cells is involved in many aspects of tumor progression, its role in tumor immune suppression remains elusive. Host cell-derived interleukin-10 (IL-10) suppressed a naturally acquired CD8 T cell-dependent antitumor response. The suppressive activity of tumor-associated Foxp3⁺CD4⁺CD25⁺ regulatory T cells (Treg) was IL-10-dependent. Neutralizing HMGB1 impaired tumor cell-promoted IL-10 production by Treg. Short hairpin RNA (shRNA)-mediated knockdown of HMGB1 (HMGB1 KD) in tumor cells did not affect tumor cell growth but uncovered naturally acquired long-lasting tumor-specific IFN-γ- or TNF-α-producing CD8 T cell responses and attenuated their ability to induce Treg leading to naturally acquired CD8 T cell- or IFN-γ-dependent tumor rejection. The data suggest that tumor cell-derived HMGB1 may suppress naturally acquired CD8 T cell-dependent antitumor immunity via enhancing Treg to produce IL-10 which is necessary for Treg-mediated immune suppression.