Blockade of the multifunctional protein HMGB1 improves cancer immunotherapy
Study conducted by researchers from the Laboratory of Experimental Pathology (GIGA-Cancer) at ULiege demonstrates that, in contrast to what was assumed, HMGB1 does not act as an "alarmin" within the tumor microenvironment but rather as a highly immunosuppressive molecule. This study is just published in the scientific journal Journal for ImmunoTherapy of Cancer.
First discovered in the 1970s for its implication in the mechanisms of transcription and chromatin remodeling, HMGB1 became, over the years, more and more interesting for the immunologists. Indeed, active or passive secretions of this protein were observed in various contexts (inflammation, infection, cancer) and the “alarmin” function of HMGB1 was demonstrated. As such, along with ATP and Calreticulin, HMGB1 is still frequently used as a marker for immunogenic cell death.
This study conducted by Michael Herfs (FNRS Research Associate), Pascale Hubert (Senior First Assistant, ULiège) and their team highlights the “dark side” of HMGB1 during carcinogenesis. Actually, in this highly oxidizing microenvironment, HMGB1 does not act as a stimulator of the immune system but rather as an immunosuppressive molecule. Associated with a poor prognosis, its extracellular presence is correlated with higher densities of myeloid-derived suppressor cells (granulocytic and monocytic), regulatory T lymphocytes and M2 macrophages. Using several inhibitors, the researchers showed that HMGB1 blockade significantly reduced cancer progression through improving anti-tumor immunity, as supported in particular by the activation of antigen-presenting cells (DCs and pDCs), the switch from M2 to M1 macrophages and the increased apoptosis of cancer cells. To conclude this study, the synergistic effect of anti-HMGB1/anti-PD-1 combination as well as the antagonist functions of oxidized and reduced forms of HMGB1 on DCs/pDCs activation were shown.
Used in traditional Japanese medicine for patients displaying a chronic infection/inflammation, inhibitors targeting HMGB1 may prove to be allies of choice for improving the current low response rate of immune checkpoint inhibitors (anti-PD-1/PD -L1) in the context of most cancers.
Reference
Pascale Hubert, Patrick Roncarati, Stephanie Demoulin, Charlotte Pilard, Marie Ancion, Celia Reynders, Thomas Lerho, Diane Bruyere, Alizee Lebeau, Coraline Radermecker, Margot Meunier, Marie-Julie Nokin, Elodie Hendrick, Olivier Peulen, Philippe Delvenne and Michael Herfs.
J Immunother Cancer. 2021 Mar;9(3):e001966. doi: 10.1136/jitc-2020-001966.
