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DNA alkylating therapy induces tumor regression through an HMGB1-mediated activation of innate immunity

Jennifer L Guerriero1, Dara Ditsworth, Joseph M Catanzaro

  • 1Graduate Program in Molecular and Cellular Biology, Stony Brook University, Stony Brook, NY 11974, USA.

Journal of Immunology (Baltimore, Md. : 1950)
|February 9, 2011
PubMed

Insights

High mobility group box 1 (HMGB1) protein is essential for DNA alkylating agents to trigger tumor regression. HMGB1 facilitates innate immune cell recruitment, crucial for chemotherapy

Area of Science:

  • Oncology
  • Immunology
  • Molecular Biology

Background:

  • Dysregulation of apoptosis contributes to cancer development and chemotherapy resistance.
  • DNA alkylating agents can induce tumor cell necrosis and regression, releasing high mobility group box 1 (HMGB1).
  • The role of HMGB1 and innate immunity in chemotherapy response remained unclear.

Purpose of the Study:

  • To investigate the role of HMGB1 and innate immunity in tumor response to DNA alkylating chemotherapy.
  • To determine if HMGB1 is essential for chemotherapy-induced tumor regression.

Main Methods:

  • Utilized an athymic mouse tumor xenograft model.
  • Compared tumor regression in response to DNA alkylating therapy in HMGB1-proficient versus HMGB1-deficient tumors.
  • Assessed innate immune cell infiltration (macrophages, neutrophils, NK cells) via histology.
  • Analyzed cytokine profiles using cytokine arrays.
  • Investigated the effect of depleting antibodies against innate immunity and HMGB1 on tumor regression.

Main Results:

  • DNA alkylating therapy caused complete tumor regression in HMGB1-proficient tumors but failed in HMGB1-deficient tumors.
  • HMGB1-deficient tumors showed impaired recruitment of innate immune cells after treatment.
  • DNA alkylating treatment suppressed pro-tumor cytokines (IL-4, IL-10, IL-13) in an HMGB1-dependent manner.
  • Loss of HMGB1 led to elevated pro-tumor cytokines upon treatment.
  • Suppression of innate immunity and HMGB1 abrogated chemotherapy-induced tumor regression.

Conclusions:

  • HMGB1 is essential for DNA alkylating agents to induce tumor regression.
  • HMGB1 mediates the recruitment of innate immune cells, which is critical for chemotherapy efficacy.
  • HMGB1 plays a key role in modulating the tumor microenvironment and immune response during chemotherapy.

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