Objective: Sarcomas are a group of rare malignancies with various subtypes. Patients with metastatic sarcoma who have failed traditional treatments can possibly achieve better prognoses from using novel therapies, including anti-programmed death-1 (PD-1)-based therapies.Methods: We retrospectively analyzed clinical data of 24 metastatic sarcoma patients from June 15, 2016 to December 30, 2019. These patients mainly received angiogenesis inhibitors combined with anti-PD-1 therapy after they became resistant to traditional treatments. Furthermore, 8 patients underwent panel DNA and whole transcript sequencing. Results: Six patients received 2 cycles of anti-PD-1 therapy and were included in the safety evaluation only group. The median follow-up time was 5.77 months. The median progression-free survival was 7.59 months, the overall response rate was 16.7％ and the disease control rate was 55.6％. Based on whole exome and transcript sequencing data, there was no association between TMB, TNB, MSI, HLA-LOH, and PD-L1 expressions and sarcoma types with clinical responses. Immunotherapy efficacy and bioinformatics analyses indicated higher intratumoral heterogeneity (ITH) in progressive disease (PD) patients and lower ITH in partial response (PR) and stable disease patients. A higher percentage of immune cell infiltration, especially monocytes, was observed in PR patients. Active stromal gene expression was increased in PD patients but decreased in PR patients. Enrichment analysis revealed that an increased TGF-β signaling pathway was reversely correlated with anti-PD-1 efficacy, while a decreased inflammatory response signaling pathway was positively correlated with anti-PD-1 efficacy. Conclusions: Our study showed PD-1 inhibitors combined with anti-angiogenesis agents were effective and well-tolerated. ITH, monocyte ratio, stroma subtypes, and the status of immune-associated signaling pathways may be related with anti-PD-1 based therapy.

Jia Lu;Ting Li;Zhichao Liao;Hui Yu;Yongtian Zhao;Haixiao Wu;Zhiwu Ren;Jun Zhao;Ruwei Xing;Sheng Teng;Yun Yang;Xiangchun Li;Kexin Chen;Jonathan Trent;Jilong Yang

Department of Bone and Soft Tissue Tumor,2Department of Infection Management,3Key Laboratory of Molecular Cancer Epidemiology,Tianjin Medical University Cancer Institute&Hospital,National Clinical Research Center for Cancer,Key Laboratory of Cancer Prevention and Therapy,Tianjin,Tianjin's Clinical Research Center for Cancer,Tianjin 300060,China;YuceBio Technology Co.,Ltd.,Shenzhen 518172,China;Department of Epidemiology and Biostatistics,Tianjin Medical University Cancer Institute&Hospital,National Clinical Research Center for Cancer,Key Laboratory of Cancer Prevention and Therapy,Tianjin,Tianjin's Clinical Research Center for Cancer,Tianjin 300060,China;Sarcoma Multidisciplinary Program,Sylvester Comprehensive Cancer Center,The University of Miami,Miami,FL 33136,USA

癌症生物学与医学（英文版）

[1]Jia Lu;Ting Li;Zhichao Liao;Hui Yu;Yongtian Zhao;Haixiao Wu;Zhiwu Ren;Jun Zhao;Ruwei Xing;Sheng Teng;Yun Yang;Xiangchun Li;Kexin Chen;Jonathan Trent;Jilong Yang-.The efficacies and biomarker investigations of anti-programmed death-1 (anti-PD-1)-based therapies for metastatic bone and soft tissue sarcoma)[J].癌症生物学与医学（英文版）,2022(06):910-930

Sarcomas

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