Autoantibodies Drive Heart Damage Caused by Concomitant Radiation and PD-1 Blockade

Area of Science:

• Immunology
• Cardiology
• Oncology

Background:

• Concurrent PD-1 blockade and thoracic radiotherapy are used for lung cancer.
• This combination therapy carries a risk of cardiotoxicity.
• Previous research indicated CD8+ T-cells mediate this cardiotoxicity.

Purpose of the Study:

• To investigate the role of humoral immunity in cardiotoxicity from combined PD-1 blockade and cardiac irradiation.
• To determine if autoantibodies contribute to cardiac tissue damage and functional decline.

Main Methods:

• Mice received cardiac irradiation and anti-PD-1 therapy.
• Cardiac autoantibody levels were measured.
• B cell-deficient mice were used to assess humoral immunity's role.
• Sera transfer experiments were conducted.
• IgG depletion was performed to evaluate antibody effects.

Main Results:

• Mice treated with combined therapy developed cardiac autoantibodies reacting with cardiac tissue.
• B cell-deficient mice were protected from cardiotoxicity.
• Transfer of autoantibody-rich sera reproduced cardiotoxicity in irradiated mice.
• IgG depletion reduced the cardiotoxic effects of the sera.

Conclusions:

• Concurrent cardiac irradiation and PD-1 blockade induce cardiac autoantibody production.
• These autoantibodies are essential for cardiotoxicity development.
• Humoral immunity, specifically autoantibodies, plays a key role in the cardiotoxicity of this combined cancer therapy.