B cells are associated with survival and immunotherapy response in sarcoma

TLDR

Soft‑tissue sarcomas are a heterogeneous group of cancers with over 50 histological subtypes, and their clinical presentation and responses to therapies such as immune checkpoint blockade vary widely. The study investigates gene expression profiles in 608 soft‑tissue sarcoma tumors across subtypes to explain this clinical variability. The authors performed an immune‑based classification of these tumors using microenvironment composition, defining five phenotypes (immune‑low A/B, immune‑high D/E, and highly vascularized C). Class E tumors, enriched in B‑cell–rich tertiary lymphoid structures, exhibited the strongest prognostic value, improved survival, and high response rates to PD‑1 blockade, confirming the clinical relevance of immune subtypes in soft‑tissue sarcoma.

Abstract

Soft-tissue sarcomas represent a heterogeneous group of cancer, with more than 50 histological subtypes1,2. The clinical presentation of patients with different subtypes is often atypical, and responses to therapies such as immune checkpoint blockade vary widely3,4. To explain this clinical variability, here we study gene expression profiles in 608 tumours across subtypes of soft-tissue sarcoma. We establish an immune-based classification on the basis of the composition of the tumour microenvironment and identify five distinct phenotypes: immune-low (A and B), immune-high (D and E), and highly vascularized (C) groups. In situ analysis of an independent validation cohort shows that class E was characterized by the presence of tertiary lymphoid structures that contain T cells and follicular dendritic cells and are particularly rich in B cells. B cells are the strongest prognostic factor even in the context of high or low CD8+ T cells and cytotoxic contents. The class-E group demonstrated improved survival and a high response rate to PD1 blockade with pembrolizumab in a phase 2 clinical trial. Together, this work confirms the immune subtypes in patients with soft-tissue sarcoma, and unravels the potential of B-cell-rich tertiary lymphoid structures to guide clinical decision-making and treatments, which could have broader applications in other diseases. Immune profiling of the tumour microenvironment of soft-tissue sarcoma identifies a group of patients with high levels of B-cell infiltration and tertiary lymphoid structures that have improved survival and a high response rate to immune checkpoint blockade therapy.