Abstract
Rhabdomyosarcomas (RMS) are rare and often lethal diseases. It is assumed that the tumor microenvironment (TME) of RMS exerts an immunosuppressive function, but there is currently no systematic analysis of the immune cells infiltrating sarcoma tissue. Focusing on two common types of RMS (alveolar [RMA] and embryonal [RME]), we performed a comprehensive immunohistochemical analysis of tumor-infiltrating immune cells in the TME. We performed a qualitative estimation of infiltrating immune cells in the tumor microenvironment by an experienced pathologist as well as a quantitative digital pathology analysis. We found that (1) manual and automatic quantification of tumor-infiltrating immune cells were consistent; (2) RME tumors showed a higher degree of immune cell infiltration than RMA tumors but (3) the number of tumor infiltrating lymphocytes was low compared to other solid tumor types; (4) microvascular density correlated with immune cell infiltration and (5) CD163 positive macrophages as well as CD54 positive microvessels were more often detected in RME than in RMA and correlated with patient overall and event free survival. Our systematic analysis provides a comprehensive view of the immune landscape of RMS which needs to be taken into account for developing immunotherapies for this rare type of cancer.
Highlights
Rhabdomyosarcoma (RMS) is a soft tissue malignancy that mainly affects children and young adults
Immune therapies are the new hopes for otherwise refractory cancers, and better knowledge of the tumor microenvironment is considered key to predict treatment outcome[24]
We performed a comprehensive quantitative digital pathology-based analysis of various intratumoral immune cells, PD1 and PD-L1 expression and microvascular features in RMA and RME with reference to the clinical outcome, from which we gained the following new findings: (1) RMA exhibited a low number of intratumoral CD3+ and CD8+ T cells, while the abundance of these cells was slightly higher among RME cases; (2) FOXP3 positive regulatory T cells were generally absent from RMA and RME; (3) CD54+ microvessels were significantly more frequent in RME than RMA and their presence was associated with higher numbers of intratumoral immune cells; (4) high numbers of intratumoral CD163+ macrophages and CD54+ microvessels were more common in RME and associated with improved survival in RME
Summary
Rhabdomyosarcoma (RMS) is a soft tissue malignancy that mainly affects children and young adults. The TME is a complex system, consisting of tumor and of endothelial cells, cancer associated fibroblasts (CAF), cytotoxic and immune suppressive immune cell infiltrates, antigen presenting cells and the extracellular matrix17 - a conglomerate that is generally called “tumor stroma”. The interactions between these constituents determine the clinical course of a solid tumor disease and the susceptibility to tumor immunotherapy[18,19]. To the best of our knowledge, this is the first study that systematically addresses the immune contexture of RMA and RME: In particular, the stainings were independently analyzed by a previously validated computer based approach[23] and an experienced pathologist, thereby combining the assessment of the pathologist with the quantitative analysis of the computer based approach
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