A chemical screen underscores the essential role of STAT1-dependent IFNγ signaling to regulate HLA-I expression in cancer cells

The presentation of neoantigens by HLA-I is essential for the recognition of tumor cells by cytotoxic T cells. Transcriptionally, HLA-I expression is regulated by interferon-dependent activation of JAK/STAT signaling. Accordingly, mutations that inactivate this pathway are one of the main causes of resistance to cancer immunotherapies. Recent evidences indicate that HLA-I expression can be induced independently of IFN-signaling by the innate immune response. In this context, we performed an image-based screen to evaluate how more than 5,000 chemicals, including all medically available drugs plus many others in advanced preclinical development, influence HLA-I expression in STAT1-deficient cells. Our screening failed to identify any significant hits, suggesting that drug-dependent modulation of HLA-I expression is strictly dependent on IFN-signaling.