Renal cancer cells acquire immune surface protein through trogocytosis and horizontal gene transfer

Abstract

Trogocytosis is an underappreciated phenomenon that shapes the immune microenvironment surrounding many types of solid tumors. The consequences of membrane-bound proteins being deposited from a donor immune cell to a recipient cancer cell via trogocytosis are still unclear. Here, we report that human clear cell renal carcinoma tumors stably express the lymphoid markers CD45, CD56, CD14, and CD16. Flow cytometry performed on fresh kidney tumors revealed consistent CD45 expression on tumor cells, as well as varying levels of the other markers mentioned previously. These results were consistent with our immunofluorescent analysis, which also revealed colocalization of lymphoid markers with carbonic anhydrase 9 (CAIX), a standard kidney tumor marker. RNA analysis showed a significant upregulation of genes typically associated with immune cells in tumor cells following trogocytosis. Finally, we show evidence of chromosomal DNA being transferred from immune cells to tumor cells during trogocytosis. This horizontal gene transfer has transcriptional consequences in the recipient tumor cell, resulting in a fusion phenotype that expressed both immune and cancer specific proteins. This work demonstrates a novel mechanism by which tumor cell protein expression is altered through the acquisition of surface membrane fragments and genomic DNA from infiltrating lymphocytes. These results alter the way in which we understand tumor-immune cell interactions and may reveal new insights into the mechanisms by which tumors develop. Additionally, further studies into trogocytosis will help push the field towards the next generation of immunotherapies and biomarkers for treating renal cell carcinoma and other types of cancers. SIGNIFICANCE STATEMENTWe have identified trogocytosis as a mechanism by which human clear cell renal carcinoma tumors acquire lymphocyte surface protein expression from tumor infiltrating immune cells. In addition to the transfer of membrane fragments, we have provided evidence to show that genomic DNA is transferred from a normal immune cell to a tumor cell during trogocytosis. This process alters the transcriptome of cancer cells such that they express significantly more mRNA for immune proteins such as the lymphocyte marker CD45 compared to tumor cells that have not undergone trogocytosis. This study provides an in-depth analysis of the interactions between cancer cells and tumor infiltrating lymphocytes, and how these interactions alter the development of human tumors.