|Publication Type||Journal Article|
|Year of Publication||2017|
|Authors||George, 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 Published||2017 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.
|PubMed Central ID||PMC5408320|
|Grant List||K08 CA188615 / CA / NCI NIH HHS / United States |
P50 CA101942 / CA / NCI NIH HHS / United States