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Immunity DOI:10.1016/j.immuni.2017.02.001

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

Publication TypeJournal Article
Year of Publication2017
AuthorsGeorge, S, Miao, D, Demetri, GD, Adeegbe, D, Rodig, SJ, Shukla, S, Lipschitz, M, Amin-Mansour, A, Raut, CP, Carter, SL, Hammerman, P, Freeman, GJ, Wu, CJ, Ott, PA, Wong, K-K, Van Allen, EM
Date Published2017 Feb 21

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.


Alternate JournalImmunity
PubMed ID28228279
PubMed Central IDPMC5408320
Grant ListK08 CA188615 / CA / NCI NIH HHS / United States
P50 CA101942 / CA / NCI NIH HHS / United States