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Melanoma cells secrete melanosomes, large extracellular vesicles that reinforce tumor growth and survival signaling. To determine whether these vesicles elicit functional humoral immunity, we immunized mice with melanoma-derived melanosomes and analyzed the resulting antibody responses. This approach induced B cell expansion and generated antibodies directed against heat shock protein 70 (HSP70) present on the surface of melanosomes. Functionally, anti-HSP70 monoclonal antibodies inhibited growth in murine B16 and human MNT-1 melanoma cells independently of immune effector cells while suppressing key transcriptional programs involved in proliferation. In vivo, passive administration of anti-HSP70 antibodies delayed tumor onset and improved survival in a prophylactic B16 model. Moreover, in patients with metastatic melanoma treated with immune checkpoint blockade, higher serum anti-HSP70 immunoglobulin G (IgG) levels were associated with complete response compared with progressive disease. Together, these findings identify an extracellular vesicle-antibody axis that constrains melanoma survival signaling and has biomarker and therapeutic implications.
Ben-Shalom et al. (Wed,) studied this question.