Spatial immunoprofiling of retroperitoneal leiomyosarcomas reveals intratumoral heterogeneity in immune cell infiltration, checkpoint molecule expression, and tertiary lymphoid structures

TL;DR

This study shows that retroperitoneal leiomyosarcomas have significant immune cell variation within the tumor, which may explain inconsistent responses to immunotherapy.

Contribution

The study reveals spatial immune heterogeneity in LMS tumors, including region-specific checkpoint molecule expression and TLS distribution.

Findings

TLSs were found only at tumor margins and varied across samples from the same tumor.

PD-1 and PD-L1 expression levels differed within individual tumors.

Anti-LAG-3 blockade affected cytokine and checkpoint molecule levels in a region-specific manner.

Abstract

Leiomyosarcoma (LMS) is a rare, aggressive cancer with limited treatment options at the metastatic stage. The response to immune checkpoint inhibitors (ICIs) is inconsistent, likely due to intratumoral heterogeneity, which is more pronounced in large tumours such as retroperitoneal LMS.

This study examined heterogeneity in four large treatment-naive LMS tumours (ten samples per tumour) by analysing immune cells, tertiary lymphoid structures (TLSs), checkpoint molecules, and cytokine secretion across different tumour regions.

Significant region-dependent differences were observed in immune components, with TLSs present only at tumour margins and inconsistently across samples from the same tumour. Expression levels of programmed cell death 1 (PD-1) and programmed death ligand 1 (PD-L1) varied within individual tumours, and shared immune patterns were identified in specific regions, including elevated indoleamine 2,3-dioxygenase 1, absence of a particular macrophage subpopulation, and reduced PD-1 and lymphocyte activation gene 3 (LAG-3) expression at organ-adjacent margins. Anti-LAG-3 blockade altered cytokine and checkpoint molecule levels in a region-specific manner.

These findings highlight substantial intratumoral heterogeneity, which may contribute to the variable response to ICI therapy. As immune checkpoint molecule expression influences treatment eligibility, multiple biopsies from different tumour regions may be necessary to assess immune infiltration accurately and guide therapy decisions.

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