title: Loss of PTEN Is Associated with Resistance to Anti-PD-1 Checkpoint Blockade Therapy in Metastatic Uterine Leiomyosarcoma.
abstract: 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.
authors.affiliation: Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA 02215, USA.
authors.forename: Suzanne
authors.initials: S
authors.lastname: George
authors.affiliation: Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA 02215, USA; Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA.
authors.forename: Diana
authors.initials: D
authors.lastname: Miao
authors.affiliation: Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA 02215, USA; Ludwig Center at Harvard, Boston, MA 02215, USA.
authors.forename: George D
authors.initials: GD
authors.lastname: Demetri
authors.affiliation: Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA 02215, USA.
authors.forename: Dennis
authors.initials: D
authors.lastname: Adeegbe
authors.affiliation: Department of Pathology, Brigham and Women's Hospital, Boston, MA 02215, USA; Center for Immuno-Oncology, Dana-Farber Cancer Institute, Boston, MA 02215, USA.
authors.forename: Scott J
authors.initials: SJ
authors.lastname: Rodig
authors.affiliation: Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA 02215, USA.
authors.forename: Sachet
authors.initials: S
authors.lastname: Shukla
authors.affiliation: Department of Pathology, Brigham and Women's Hospital, Boston, MA 02215, USA.
authors.forename: Mikel
authors.initials: M
authors.lastname: Lipschitz
authors.affiliation: Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA.
authors.forename: Ali
authors.initials: A
authors.lastname: Amin-Mansour
authors.affiliation: Department of Surgery, Brigham and Women's Hospital, Boston, MA 02215, USA.
authors.forename: Chandrajit P
authors.initials: CP
authors.lastname: Raut
authors.affiliation: 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.
authors.forename: Scott L
authors.initials: SL
authors.lastname: Carter
authors.affiliation: Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA 02215, USA; Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA.
authors.forename: Peter
authors.initials: P
authors.lastname: Hammerman
authors.affiliation: Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA 02215, USA; Center for Immuno-Oncology, Dana-Farber Cancer Institute, Boston, MA 02215, USA.
authors.forename: Gordon J
authors.initials: GJ
authors.lastname: Freeman
authors.affiliation: 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.
authors.forename: Catherine J
authors.initials: CJ
authors.lastname: Wu
authors.affiliation: Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA 02215, USA.
authors.forename: Patrick A
authors.initials: PA
authors.lastname: Ott
authors.affiliation: Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA 02215, USA.
authors.forename: Kwok-Kin
authors.initials: KK
authors.lastname: Wong
authors.affiliation: 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.
authors.forename: Eliezer M
authors.initials: EM
authors.lastname: Van Allen
mesh_terms: D061067:Antibodies, Monoclonal, Humanized / Q000627:therapeutic use; D000970:Antineoplastic Agents / Q000627:therapeutic use; D004252:DNA Mutational Analysis; D019008:Drug Resistance, Neoplasm / Q000235:genetics*; D005260:Female; D020869:Gene Expression Profiling; D006801:Humans; D007890:Leiomyosarcoma / Q000188:drug therapy / Q000235:genetics / Q000473:pathology*; D008875:Middle Aged; D009154:Mutation; D051059:PTEN Phosphohydrolase / Q000235:genetics*; D061026:Programmed Cell Death 1 Receptor / Q000037:antagonists & inhibitors; D059467:Transcriptome; D014594:Uterine Neoplasms / Q000188:drug therapy / Q000235:genetics / Q000473:pathology*
chemical_list: D061067:Antibodies, Monoclonal, Humanized; D000970:Antineoplastic Agents; C105992:PDCD1 protein, human; D061026:Programmed Cell Death 1 Receptor; C582435:pembrolizumab; D051059:PTEN Phosphohydrolase; C494929:PTEN protein, human
keywords: exceptional response; immune checkpoint; immunotherapy; neoantigen; sarcoma; whole-exome sequencing; whole-transcriptome sequencing