IFN-γ signature enables selection of neoadjuvant treatment in patients with stage III melanoma

J Exp Med. 2023 May 1;220(5):e20221952. doi: 10.1084/jem.20221952. Epub 2023 Mar 15.


Neoadjuvant ipilimumab + nivolumab has demonstrated high pathologic response rates in stage III melanoma. Patients with low intra-tumoral interferon-γ (IFN-γ) signatures are less likely to benefit. We show that domatinostat (a class I histone deacetylase inhibitor) addition to anti-PD-1 + anti-CTLA-4 increased the IFN-γ response and reduced tumor growth in our murine melanoma model, rationalizing evaluation in patients. To stratify patients into IFN-γ high and low cohorts, we developed a baseline IFN-γ signature expression algorithm, which was prospectively tested in the DONIMI trial. Patients with stage III melanoma and high intra-tumoral IFN-γ scores were randomized to neoadjuvant nivolumab or nivolumab + domatinostat, while patients with low IFN-γ scores received nivolumab + domatinostat or ipilimumab + nivolumab + domatinostat. Domatinostat addition to neoadjuvant nivolumab ± ipilimumab did not delay surgery but induced unexpected severe skin toxicity, hampering domatinostat dose escalation. At studied dose levels, domatinostat addition did not increase treatment efficacy. The baseline IFN-γ score adequately differentiated patients who were likely to benefit from nivolumab alone versus patients who require other therapies.

Publication types

  • Randomized Controlled Trial
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Antineoplastic Combined Chemotherapy Protocols / therapeutic use
  • Humans
  • Interferon-gamma
  • Ipilimumab / adverse effects
  • Ipilimumab / therapeutic use
  • Melanoma* / pathology
  • Melanoma, Cutaneous Malignant
  • Mice
  • Neoadjuvant Therapy
  • Nivolumab / adverse effects
  • Skin Neoplasms* / drug therapy
  • Skin Neoplasms* / pathology


  • domatinostat
  • Nivolumab
  • Ipilimumab
  • Interferon-gamma