Publication date: 21 February 2017
Source:Immunity, Volume 46, Issue 2
Author(s): Suzanne George, Diana Miao, George D. Demetri, Dennis Adeegbe, Scott J. Rodig, Sachet Shukla, Mikel Lipschitz, Ali Amin-Mansour, Chandrajit P. Raut, Scott L. Carter, Peter Hammerman, Gordon J. Freeman, Catherine J. Wu, Patrick A. Ott, Kwok-Kin Wong, Eliezer M. Van Allen
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.
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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 was associated with induction of an immunosuppressive microenvironment.http://ift.tt/2lBHksk
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