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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
JournalImmunity
Volume46
Issue2
Pages197-204
Date Published2017 Feb 21
ISSN1097-4180
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.

DOI10.1016/j.immuni.2017.02.001
Pubmed

http://www.ncbi.nlm.nih.gov/pubmed/28228279?dopt=Abstract

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