High mobility group B1 and N1 (HMGB1 and HMGN1) are associated with tumor-infiltrating lymphocytes in HER2-positive breast cancers

Hee Jin Lee, Joo Young Kim, In Hye Song, In Ah Park, Jong Han Yu, Jin-Hee Ahn, Gyungyub Gong

Although the prognostic and predictive significance of tumor-infiltrating lymphocytes (TILs) in HER2-positive breast cancers has been established, the drivers of TIL influx remain unclear. We tested whether potential triggers for this response could include high mobility group B1 and N1 (HMGB1 and HMGN1) proteins, which are immunogenic damage-associated molecular pattern molecules. We evaluated TILs and the immunohistochemical expression of HMGB1 and HMGN1 in 447 HER2-positive breast cancer tissues. Normal luminal cells exhibited nuclear expression of HMGB1 and HMBN1. The nuclear and cytoplasmic expression levels of HMG proteins showed a significant inverse correlation (rho = -0.150, p = 0.001 for HMGB1; rho = -0.247, p < 0.001 for HMGN1). Low levels of HMGB1 and HMGN1 nuclear expression were identified in 185 (41.4 %) and 208 (46.5 %) cases, respectively. High levels of cytoplasmic HMGB1 and HMGN1 expression were identified in 107 (23.9 %) and 49 (11.0 %) cases, respectively. High cytoplasmic expression of HMG proteins was significantly associated with a high histological grade, high levels of TILs, peritumoral lymphocytic infiltration, and tertiary lymphoid structures in HER2-positive breast cancer tissues. Tumors with low levels of cytoplasmic HMGB1 and HMGN1 showed significantly lower levels of TILs than those with high levels of each or both HMG proteins. However, the nuclear or cytoplasmic expression of either HMG protein was not found to be significantly associated with survival. High levels of cytoplasmic HMGB1 and HMGN1 protein expression correlated with high levels of TILs in HER2-positive breast cancers. The manipulation of HMGB1 and HMGN1 could represent an immunotherapeutic approach to promote TIL influx into a tumor.