188P - Integration of immunohistochemistry and transcriptomics reveals new insights into the immune landscape of soft-tissue sarcomas

Background

Soft tissue sarcomas (STS) are a group of rare and heterogeneous tumors with different clinical and biological behaviors. Better prognosis has been associated to an inflamed tumor microenvironment (TME) characterized by the presence of tertiary lymphoid structures (TLS) and B cells. However, the cellular and molecular mechanisms underlying these clinical associations have not been elucidated yet.

Methods

TME composition and TLS quantification were assessed by sequential IHC with αCD3, αCD20, αCD23 and αCD68 antibodies on specimens obtained from patients with primary or locally recurrent STS enrolled and treated at the Careggi Hospital (RESEARCH study). TME transcriptomic profiling was performed using the nCounter Immunology Panel by NanoString. RNA-sequencing and clinical data for 206 STS patients were retrieved from the TCGA SARC project.

Results

IHC of 23 treatment-naïve STS specimens showed higher TLS density and incidence in the group of non-recurrent patients (11/15) compared to patients developing recurrence (2/8; P=0.039). CD8⁺ T cell, CD20⁺ B cell and CD23⁺ follicular dendritic cell densities are higher in the TME of TLS⁺ STS. CD20 and CD23 (but not CD8) expression is associated to improved recurrence-free survival (RFS) and overall survival (OS) in our cohort. Transcriptomic analysis of 31 treatment-naïve STSs showed that high expression of genes discriminating for germinal center (GC) B cells correlated to the upregulation of Th17-related genes, and decreased expression of M2-like tumor-associated macrophages (TAMs)-related genes. High expression of GC B cell- and Th17 differentiation-related signatures showed associations to longer RFS in our cohort, and to improved OS in the TCGA SARC cohort. Analysis of 5 samples obtained after neoadjuvant radiotherapy (RT) showed reduced expression of IL17A and GC B-related genes while increased TAM-related gene expression, compared to paired biopsies obtained before RT.

Conclusions

Our data identified a prognostic value for Th17-related genes, suggest a potential crosstalk between GC B cells and Th17 cells in coordinating antitumor immune responses, and a potential role for M2-like TAMs (and RT) in inhibiting TLS formation in STS.

Clinical trial identification

Editorial acknowledgement

Legal entity responsible for the study

The authors.

Funding

Has not received any funding.

Disclosure

All authors have declared no conflicts of interest.