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.
Author Info: (1) Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA 02215, USA. (2) Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA 02215, USA; Br
Author Info: (1) Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA 02215, USA. (2) Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA 02215, USA; Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA. (3) Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA 02215, USA; Ludwig Center at Harvard, Boston, MA 02215, USA. (4) Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA 02215, USA. (5) Department of Pathology, Brigham and Women's Hospital, Boston, MA 02215, USA; Center for Immuno-Oncology, Dana-Farber Cancer Institute, Boston, MA 02215, USA. (6) Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA 02215, USA. (7) Department of Pathology, Brigham and Women's Hospital, Boston, MA 02215, USA. (8) Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA. (9) Department of Surgery, Brigham and Women's Hospital, Boston, MA 02215, USA. (10) Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA 02215, USA; Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA; Center for Cancer Precision Medicine, Dana-Farber Cancer Institute, Boston, MA 02215, USA. (11) Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA 02215, USA; Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA. (12) Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA 02215, USA; Center for Immuno-Oncology, Dana-Farber Cancer Institute, Boston, MA 02215, USA. (13) Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA 02215, USA; Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA; Center for Immuno-Oncology, Dana-Farber Cancer Institute, Boston, MA 02215, USA. (14) Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA 02215, USA. (15) Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA 02215, USA. (16) Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA 02215, USA; Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA; Center for Cancer Precision Medicine, Dana-Farber Cancer Institute, Boston, MA 02215, USA. Electronic address: eliezerm_vanallen@dfci.harvard.edu.
