The efficacies and biomarker investigations of anti-programmed death-1 (anti-PD-1)-based therapies for metastatic bone and soft tissue sarcoma

Abstract

Objective: Sarcomas are a group of rare malignancies with various subtypes. Patients with metastatic sarcoma who have failedtraditional 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 traditionaltreatments. 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 medianfollow-up time was 5.77 months. The median progression-free survival was 7.59 months, the overall response rate was 16.7% and thedisease 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 bioinformaticsanalyses 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 anincreased TGF-β signaling pathway was reversely correlated with anti-PD-1 efficacy, while a decreased inflammatory responsesignaling 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.