High-dimensional spatial profiling of the hepatocellular carcinoma tumor microenvironment reveals spatial immune types informing immune checkpoint inhibitor therapy response

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Introduction Hepatocellular carcinomas (HCC) can be grouped into distinct immune subtypes according to their molecular profiles. However, clinical translation, especially in the context of immune checkpoint inhibitor (ICI) therapy, is lacking, which may be due to the negligence of spatial context. Thus, we set out to characterize the HCC TME on a spatially resolved and high-dimensional level using imaging mass cytometry (IMC). Methods We performed IMC analysis using a 41-marker panel on FFPE sections of 54 HCC patients with regions of interested spanning the tumor, interface and adjacent liver. After channel normalization and cell segmentation, we clustered single-cells and identified immune neighborhoods based on spatial immune cell interactions. We reapplied the same workflow to a validation cohort of 42 HCC patients that received ICI based therapies after tumor biopsy or resection. Results We identified distinct tumor immune microenvironments based on the quantity and composition of infiltrating immune cells. Specifically we distinguished three major subtypes: immune-depleted, immune-intermediate and immune-enriched. We observed a differential organization of the TME and the interface area between spatial immune types. Unsupervised neighborhood detection identified three immune neighborhoods that correlated with spatial immune types. Immune types were not clearly connected to known HCC etiologies or frequent mutations but correlated with progression-free survival under ICI based therapies. Conclusion In sum, our in-depth spatial analysis successfully captured the immune heterogeneity of HCC patients. Spatial immune types may be reflective of different immune evasive strategies of the corresponding tumor and represent a potential novel biomarker for ICI based therapies. Publication History Article published online: 23 January 2024 © 2024. Thieme. All rights reserved. Georg Thieme Verlag Rüdigerstraße 14, 70469 Stuttgart, Germany

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