Distinct immunologic patterns of response and resistance to anti-PD-1/PD-L1-based immunotherapy in patients with soft tissue sarcoma

Abstract

Introduction: Chemotherapy remains the standard of care for metastatic soft tissue sarcoma (STS), but clinical benefit is modest. Immune checkpoint inhibitors (ICIs), such as anti-programmed cell death 1 (PD-1) and anti-cytotoxic T-lymphocyte antigen 4 (CTLA-4), have transformed cancer treatment, yet their efficacy in STS is variable and largely confined to undifferentiated pleomorphic sarcoma (UPS) and dedifferentiated liposarcoma (LPS). Reliable biomarkers to predict ICI response in STS are understudied and currently lacking. Methods: We examined mutation profiles and analysed longitudinal blood samples from STS patients (n=13) treated with anti-PD-1/PD-L1–based therapy to identify molecular features and circulating immune correlates of ICI efficacy. To gain deeper insight, single-cell RNA sequencing was performed on peripheral blood mononuclear cells (PBMCs) from a patient with prolonged stable disease (>6 months). Results: Complete blood counts and PBMC profiling demonstrated that elevated circulating lymphoid cells were associated with response, whereas enrichment of innate immune populations, particularly neutrophils and monocytes, correlated with non-response. Single-cell RNA sequencing of PBMCs from a patient with prolonged stable disease revealed dynamic shifts in monocyte and CD8 T cell phenotypes and inflammatory signalling pathways, which paralleled radiological tumour regression and subsequent progression. Discussion: Our findings highlight peripheral immune profiles as candidate biomarkers for predicting and monitoring ICI efficacy in STS. Incorporating these immune markers could refine patient selection, reduce unnecessary toxicity, and support adaptive treatment strategies for patients with this rare and heterogenous cancer.