CD4+ T Cells Contribute to the Remodeling of the Microenvironment Required for Sustained Tumor Regression upon Oncogene Inactivation

SummaryOncogene addiction is thought to occur cell autonomously. Immune effectors are implicated in the initiation and restraint of tumorigenesis, but their role in oncogene inactivation-mediated tumor regression is unclear. Here, we show that an intact immune system, specifically CD4+ T cells, is required for the induction of cellular senescence, shutdown of angiogenesis, and chemokine expression resulting in sustained tumor regression upon inactivation of the MYC or BCR-ABL oncogenes in mouse models of T cell acute lymphoblastic lymphoma and pro-B cell leukemia, respectively. Moreover, immune effectors knocked out for thrombospondins failed to induce sustained tumor regression. Hence, CD4+ T cells are required for the remodeling of the tumor microenvironment through the expression of chemokines, such as thrombospondins, in order to elicit oncogene addiction.

Graphical AbstractFigure optionsDownload high-quality image (289 K)Download as PowerPoint slideHighlights
► Oncogene addiction involves both cell autonomous and nonautonomous mechanisms
► An immune system is required for sustained tumor regression upon inactivation of oncogenes (MYC or BCR-ABL)
► CD4+ T cells regulate cellular senescence and angiogenesis in the tumor microenvironment
► TSP-1 secretion from immune cells is required for sustained tumor regression upon inactivation of an oncogene