Drug screens find no workaround for cancer's immune-evasion weakness
Researchers tested over 5,000 drugs and compounds to find alternatives for reactivating immune recognition of tumors, but failed completely. The finding confirms that cancer cells escaping immunotherapy largely do so by disabling a single critical pathway—suggesting no easy pharmaceutical shortcut exists for patients with resistant tumors.
Originaltitel: 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.