title: DNA alkylating therapy induces tumor regression through an HMGB1-mediated activation of innate immunity.
abstract: Dysregulation of apoptosis is associated with the development of human cancer and resistance to anticancer therapy. We have previously shown in tumor xenografts that DNA alkylating agents induce sporadic cell necrosis and regression of apoptosis-deficient tumors. Sporadic tumor cell necrosis is associated with extracellular release of cellular content such as the high mobility group box 1 (HMGB1) protein and subsequent recruitment of innate immune cells into the tumor tissue. It remained unclear whether HMGB1 and the activation of innate immunity played a role in tumor response to chemotherapy. In this study, we show that whereas DNA alkylating therapy leads to a complete tumor regression in an athymic mouse tumor xenograft model, it fails to do so in tumors deficient in HMGB1. The HMGB1-deficient tumors have an impaired ability to recruit innate immune cells including macrophages, neutrophils, and NK cells into the treated tumor tissue. Cytokine array analysis reveals that whereas DNA alkylating treatment leads to suppression of protumor cytokines such as IL-4, IL-10, and IL-13, loss of HMGB1 leads to elevated levels of these cytokines upon treatment. Suppression of innate immunity and HMGB1 using depleting Abs leads to a failure in tumor regression. Taken together, these results indicate that HMGB1 plays an essential role in activation of innate immunity and tumor clearance in response to DNA alkylating agents.
authors.affiliation: Graduate Program in Molecular and Cellular Biology, Stony Brook University, Stony Brook, NY 11974, USA.
authors.forename: Jennifer L
authors.initials: JL
authors.lastname: Guerriero
authors.forename: Dara
authors.initials: D
authors.lastname: Ditsworth
authors.forename: Joseph M
authors.initials: JM
authors.lastname: Catanzaro
authors.forename: Gregory
authors.initials: G
authors.lastname: Sabino
authors.forename: Martha B
authors.initials: MB
authors.lastname: Furie
authors.forename: Richard R
authors.initials: RR
authors.lastname: Kew
authors.forename: Howard C
authors.initials: HC
authors.lastname: Crawford
authors.forename: Wei-Xing
authors.initials: WX
authors.lastname: Zong
mesh_terms: D000818:Animals; D018906:Antineoplastic Agents, Alkylating / Q000494:pharmacology* / Q000627:therapeutic use; D002461:Cell Line, Transformed; D045744:Cell Line, Tumor; D002478:Cells, Cultured; D019008:Drug Resistance, Neoplasm / Q000276:immunology*; D057809:HEK293 Cells; D024243:HMGB1 Protein / Q000172:deficiency / Q000378:metabolism / Q000502:physiology*; D006801:Humans; D007113:Immunity, Innate / Q000276:immunology*; D008297:Male; D051379:Mice; D008819:Mice, Nude; D009336:Necrosis; D009374:Neoplasms, Experimental / Q000276:immunology* / Q000473:pathology / Q000517:prevention & control*; D011897:Random Allocation
chemical_list: D018906:Antineoplastic Agents, Alkylating; D024243:HMGB1 Protein