Autophagy-mediated Secretion of Intracellular Antigens Co-opts Antibody Responses to Drive Neutrophil-Dependent Tumor Progression.

Autophagy-driven secretion of intracellular antigens (SICAs) in a spontaneous hepatocellular carcinoma model generates ALDH1L1 autoantibodies that form immune complexes and recruit neutrophils to drive tumor progression.

• Why it matters: It is unclear how hidden intracellular proteins become targets of tumor-associated antibodies and what roles tumor-infiltrating B cell–encoded autoantibodies play in shaping tumor immunity.
• What they did: Monoclonal antibodies cloned from tumor-infiltrating B cells in a spontaneous HCC model were used to define SICAs, showing HSP90-mediated autophagy-dependent unconventional secretion of cytosolic proteins like ALDH1L1.
• The result: Immune complexes at the tumor site recruit and reprogram neutrophils into tumor-associated neutrophils, and this effect is abolished by neutrophil depletion or loss of Fcγ receptor binding, with the SICA-autoantibody response conserved across HCC patients and extended to lung, breast, and cervical cancers.

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