Suzanne George 1 , Diana Miao 1 , 3 , George D. Demetri 1 , Dennis Adeegbe 1 , Scott J. Rodig 4 , 5 , Sachet Shukla 1 , Mikel Lipschitz 4 , Ali Amin-Mansour 3 , Chandrajit P. Raut 6 , Scott L. Carter 1 , 3 , 7 , Peter Hammerman 1 , 3 , Gordon J. Freeman 1 , 5 , Catherine J. Wu 1 , 3 , 5 , Patrick A. Ott 1 , Kwok-Kin Wong 1 , Eliezer M. Van Allen 1 , 3 , 7
21 February 2018
Response to immune checkpoint blockade in mesenchymal tumors is poorly characterized, but immunogenomic dissection of these cancers may inform immunotherapy mediators. We identified a treatment-naïve patient with metastatic uterine leiomyosarcoma who experienced complete tumor remission for >2 years on anti-PD-1 (pembrolizumab) monotherapy. We analyzed 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, with sparse PD-L1 staining. PD-1 + cell infiltration significantly decreased in the resistant tumor (p=0.02). 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 mutation and reduced expression of genes encoding neoantigens as potential mediators of resistance to immune checkpoint therapy.
George et al. report an exceptional responder to anti-PD-1 monotherapy in uterine leiomyosarcoma and propose mediators of treatment sensitivity and resistance. Neoantigen-directed immunoreactivity was associated with sensitivity to anti-PD-1 monotherapy, whereas resistance was associated with reduction in neoantigen expression consistent with immune evasion, and biallelic PTEN loss associated with induction of an immunosuppressive microenvironment.