Constitutive or acquired resistance is a major problem limiting the clinical success of anticancer immunotherapies targeting the PD-1/PD-L1 interaction. Here, we report that the molecular chaperone HSP90 is a key mediator of IFNγ-induced adaptive immune resistance. An unbiased screen of 17 cancer cell lines or primary cancer cells identified novel metabolic agents, especially HSP90 inhibitors, that blocked the upregulation of immune checkpoints (IDO1 and PD-L1) induced by IFNγ. Subsequent quantitative mass spectrometry combined with functional rescue analysis revealed that IFNγ-induced immune checkpoint expression requires increased protein stability of the transcription factor STAT1, mediated by the HSP90–SUGT1 chaperone complex. Expression of dominant-negative HSP90 (D88N) resulted in inhibition of STAT1-mediated IFNγ signaling. The upregulation of IDO1 in cancer cells acted as an immunosuppressive feedback mechanism to limit the proliferation and function of cytotoxic CD8+ T lymphocytes through iron-dependent kynurenine production and subsequent TSPAN5-mediated kynurenine secretion. The effectiveness and safety of combinations of anti-PD-1 immunotherapy with iron chelation or pharmacologic inhibitors of HSP90 or IDO1 was confirmed in xenograft, orthotopic, and transgenic mouse models of pancreatic cancer. These findings support the rationale for future clinical trials in which widely used immunotherapies are combined with additional molecules that intercept resistance by iron chelation, IDO1 inhibition, or HSP90 neutralization.

Significance:

This study reveals an HSP90-centric, iron-modulated mechanism that confers immunosuppression, offering potential therapeutic targets for interfering with acquired resistance to the most prevalent anticancer immunotherapies.

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