期刊
IMMUNITY
卷 46, 期 2, 页码 197-204出版社
CELL PRESS
DOI: 10.1016/j.immuni.2017.02.001
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资金
- BroadIgnite
- BroadNext10
- Catherine England Leiomyosarcoma Research Fund
- Ludwig Center at Harvard
- Erica Kaitz LMS RESEARCH NOW Fund
- NIH [K08CA188615, P50CA101942]
- Alexandra J. Miliotis Pediatric Oncology Research Fund
- Howard Hughes Medical Institute Medical Research Fellowship
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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