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.