Endoglin (CD105) overexpression is associated with an immunosuppressive tumor microenvironment in murine lung cancer models and human lung adenocarcinoma

Abstract

Abstract The tumor microenvironment (TME) is a major determinant of tumor response to different therapies, especially immunotherapy. Tumors with high CD8 + T-cell infiltration that respond well to immunotherapy are referred to as “hot” tumors, whereas “cold” tumors, with an immunosuppressive microenvironment, respond less effectively to this therapy. Endoglin (CD105) plays a critical role in angiogenesis, and its overexpression has been associated with a poorer prognosis in several types of cancer. This study aims to investigate whether high endoglin levels are associated with a cold microenvironment in tumors. Transgenic mice ubiquitously overexpressing human endoglin ( ENG + ) and wild-type C57BL/6J mice (WT) were used to analyze the TME in a Lewis Lung Carcinoma (LLC) subcutaneous xenograft model and in a lung cancer model. Tumors developed in ENG + mice exhibited increased hypoxia, reduced CD8 + T-cell infiltration and an increased presence of immunosuppressive cells, such as M2 TAMs and Treg, compared to WT tumors. Thus, these tumors can be categorized as cold tumors. In addition, the analysis of the TME and endoglin expression in human lung adenocarcinoma samples showed that cold tumors have higher endoglin levels than hot tumors. These findings suggest that a hypoxic and immunosuppressive microenvironment may contribute to the poorer prognosis of tumors with high levels of this protein. This study highlights the potential of endoglin as a marker to predict the response to immunotherapy and to guide personalized treatment strategies in cancer patients.