Blood-based biomarkers in soft tissue sarcoma: Implications for immune checkpoint inhibitor therapy

Abstract

Soft tissue sarcoma (STS) is a rare and heterogeneous cancer, comprising approximately 1% of all adult cancers and 7%-15% of all childhood cancers. In the advanced stages, chemotherapy remains the standard-of-care, but efficacy is limited, with a response rate of 15%-30%, and responses are often short-lived, with median progression-free survival typically of 6 months. Moreover, patients with advanced or metastatic STS have a median overall survival of only 18-24 months. Immune checkpoint inhibitors (ICI) have revolutionized the treatment of various cancers including melanoma and non-small cell lung cancer (NSCLC). Emerging evidence from recent clinical trials indicates that certain STS subtypes may be amenable to immunotherapy. A critical challenge, however, is identifying biomarkers that can accurately predict and enable monitoring of ICI responses, to enable better patient selection and to improve outcomes. This narrative review highlights the current research gap in the treatment of STS patients with ICI therapy, particularly the absence of reliable blood-based biomarkers to predict ICI response. In this review, we examine current clinical trials investigating the efficacy of ICI therapy in patients with STS and summarise circulating immune-related prognostic biomarkers in STS, including haematological indices, peripheral blood mononuclear cells, circulating proteins and DNA, and evaluate their potential as predictive biomarkers for ICI therapy. We propose that these immune-associated molecules may serve as predictive biomarkers to differentiate and monitor ICI response, thus presenting opportunities for personalised treatment for patients with STS.

Keywords: circulating; clinical trials; immunotherapy; predictive; programmed cell death protein 1 (PD‐1).

FIGURE 1

Types of blood‐based biomarkers in patients with soft tissue sarcoma. Tumour and various subsets of immune cells, including those of the myeloid (neutrophils, eosinophils, basophils, monocytes, macrophages, myeloid derived suppressor cells, dendritic cells, platelets, red blood cells) and lymphoid (CD4 and CD8 T cells, NK cells, and B cells) origin, proteins and nucleic acids (DNA, methylated DNA, microRNA, long non‐coding RNA) can be detected in blood biopsies of STS patients and may serve as blood‐based prognostic and predictive biomarkers.

FIGURE 2

The prognostic value of peripheral blood immune cell subtypes, proteins and DNA in soft tissue sarcoma. Higher levels of NKG2D⁺ CD8⁺ T cells and LMR have been associated with good prognosis (green) while elevated levels of TIM‐3⁺ CD8⁺ T cells, LAG‐3⁺ CD8⁺ T cells, M‐MDSCs, circulating tumour cells, circulating DNA (methylated or nonmethylated), MR, NLR, PLR, IL‐6, IL‐8 are associated with poor prognosis (red). Abbreviations are as follows; M‐MDSCs, monocyte‐myeloid derived suppressor cells; NKG2D, natural killer group 2 member D; TIM‐3, T cell immunoglobulin and mucin domain‐containing protein 3; LAG‐3, lymphocyte‐activation gene 3; MR, monocyte ratio; NLR, neutrophil‐to‐lymphocyte ratio; PLR, platelet‐to‐lymphocyte ratio; LMR, lymphocyte‐to‐monocyte ratio; IL‐6, interleukin‐6; IL‐8, interleukin‐8.