Loss of PTEN Is Associated with Resistance to Anti-PD-1 Checkpoint Blockade Therapy in Metastatic Uterine Leiomyosarcoma

Immunity. 2017 Feb 21;46(2):197-204. doi: 10.1016/j.immuni.2017.02.001.


Response to immune checkpoint blockade in mesenchymal tumors is poorly characterized, but immunogenomic dissection of these cancers could inform immunotherapy mediators. We identified a treatment-naive patient who has metastatic uterine leiomyosarcoma and has experienced complete tumor remission for >2 years on anti-PD-1 (pembrolizumab) monotherapy. We analyzed the primary tumor, the sole treatment-resistant metastasis, and germline tissue to explore mechanisms of immunotherapy sensitivity and resistance. Both tumors stained diffusely for PD-L2 and showed sparse PD-L1 staining. PD-1+ cell infiltration significantly decreased in the resistant tumor (p = 0.039). Genomically, the treatment-resistant tumor uniquely harbored biallelic PTEN loss and had reduced expression of two neoantigens that demonstrated strong immunoreactivity with patient T cells in vitro, suggesting long-lasting immunological memory. In this near-complete response to PD-1 blockade in a mesenchymal tumor, we identified PTEN mutations and reduced expression of genes encoding neoantigens as potential mediators of resistance to immune checkpoint therapy.

Keywords: exceptional response; immune checkpoint; immunotherapy; neoantigen; sarcoma; whole-exome sequencing; whole-transcriptome sequencing.

Publication types

  • Case Reports
  • Clinical Trial, Phase II
  • Research Support, Non-U.S. Gov't
  • Research Support, N.I.H., Extramural

MeSH terms

  • Antibodies, Monoclonal, Humanized / therapeutic use
  • Antineoplastic Agents / therapeutic use
  • DNA Mutational Analysis
  • Drug Resistance, Neoplasm / genetics*
  • Female
  • Gene Expression Profiling
  • Humans
  • Leiomyosarcoma / drug therapy
  • Leiomyosarcoma / genetics
  • Leiomyosarcoma / pathology*
  • Middle Aged
  • Mutation
  • PTEN Phosphohydrolase / genetics*
  • Programmed Cell Death 1 Receptor / antagonists & inhibitors
  • Transcriptome
  • Uterine Neoplasms / drug therapy
  • Uterine Neoplasms / genetics
  • Uterine Neoplasms / pathology*


  • Antibodies, Monoclonal, Humanized
  • Antineoplastic Agents
  • PDCD1 protein, human
  • Programmed Cell Death 1 Receptor
  • pembrolizumab
  • PTEN Phosphohydrolase
  • PTEN protein, human