Stem/progenitor cell marker expression in clear cell renal cell carcinoma: a potential relationship with the immune microenvironment to be explored

Background: Clear cell renal cell carcinoma (ccRCC) is a markedly heterogeneous disease in many aspects, including the tumour microenvironment. Our previous study showed the importance of the tumour microenvironment in ccRCC xeno-transplant success rates. In order to better understand the potential relationship between TICs and the immune microenvironment, we employed a multi-modal approach, examining RNA and protein expression (flow cytometry, immunohistochemistry).

Methods: We first examined the gene expression pattern of 18 stem/progenitor marker genes in the cancer genome atlas (TCGA) ccRCC cohort. Flow cytometry was next employed to examine lineage-specific expression levels of stem/progenitor markers and immune population makeup in six, disaggregated, primary ccRCC specimens. Immunohistochemistry was performed on a commercial ccRCC tissue microarray (TMA).

Results: The 18 genes differed with respect to their correlation patterns with one another and to their prognostic significance. By flow cytometry, correlating expression frequency of 12 stem/progenitor markers and CD10 resulted in two clusters-one with CD10 (marker of proximal tubular differentiation), and second cluster containing mostly mesenchymal stem cell (MSC) markers, including CD146. In turn, these clusters differed with respect to their correlation with different CD45⁺ lineage markers and their expression of immune checkpoint pathway proteins. To confirm these findings, four stem/progenitor marker expression patterns were compared with CD4, CD8 and CD20 in a ccRCC TMA which showed a number of similar trends with respect to frequency of the different tumour-infiltrating leukocytes.

Conclusion: Taken together, we observed heterogeneous but patterned expression levels of different stem/progenitor markers. Our results suggest a non-random relationship between their expression patterns with the immune microenvironment populations in ccRCC.