Citations 1
Distinct Sarcoma Microenvironments Predict Benefit from Addition of Pembrolizumab to Preoperative Radiotherapy and Surgery in SU2C-SARC032
Testa, Stefano , Himes, Jonathon E. , Nouth, Serey C.L. , Pierpoint, Matthew , Binkley, Michael S., Hong, Angela , Brigman, Brian E. , Riedel, Richard F. , Kirsch, David G. , Moding, Everett J. , Moding, Everett J , Riedel, Richard F , Subramanian, Ajay , Ballman, Karla V. , Heise, Rachel S. , Nemat‐Gorgani, Neda , Sears, Timothy J. , Binkley, Michael S. , Kalbasi, Anusha K. , Corcoran, David L. , Rijn, Matt van de , Mowery, Yvonne Marie , Weinhold, Kent J.
No container title available | November 4, 2025 | Volume: No volume available | Issue: No issue available | Pages: No page available
Abstract The addition of pembrolizumab to preoperative radiotherapy (RT) improved disease-free survival (DFS) for patients with stage III undifferentiated pleomorphic sarcoma (UPS) and dedifferentiated/pleomorphic liposarcoma (LPS) in the randomized SU2C-SARC032 trial. To precisely identify patients who benefit from pembrolizumab and RT, we performed comprehensive multi-omics profiling of pre- and post-treatment tumor and blood samples, including bulk RNA-seq, flow cytometry, and cytometry by time of flight. Additionally, we built a single-cell RNA-seq atlas spanning 65,786 cells from UPS and LPS to recover single-cell states in bulk tumor samples using digital cytometry. Two opposing tumor microenvironments (TMEs), immune-cold sarcoma ecotype 1 (SE1) and immune-hot sarcoma immune class E (SIC E), benefited from pembrolizumab. Pembrolizumab combined with RT caused an overall increase in activated CD8 + T cells, CD56 low NK cells, and T cell receptor diversity, while diminishing matrix-remodeling stromal cells and sarcoma cells. Our findings identify different mechanisms of response to pembrolizumab in localized, high-risk UPS/LPS and suggest that sarcoma TME signatures may identify patients most likely to benefit from adding pembrolizumab to preoperative RT.