Macrophages and antigen-presenting cells are important parts of the innate immune system as they fend off invading microbes, produce cytokines, activate other leukocytes and are implicated in the resolution of inflammatory processes and tissue remodeling. They have been found to contribute to tumor progression as they undergo phenotypic conversion from a ‘classical’ inflammatory state (M1) into an ‘alternatively’ activated, tumor tolerating state (M2). In our previous work we could show that the PI3K/PTEN signaling pathway plays a role in this fate decision process. Deletion of PTEN in myeloid cells leading to sustained PI3K activation results in an M2-like phenotype characterized by an increased release of anti-inflammatory factors.
Alternative activation of myeloid cells is beneficial in acute models of infection and inflammation, but a diminished innate immune response could be detrimental in tumor development since tumor-associated macrophages show an immune-suppressive, M2-like phenotype. To address the question whether myeloid PTEN plays a role in tumor immune surveillance, we applied a model of colitis associated colon cancer (CAC) in myeloid cell specific PTEN-deficient mice.
PTENfl/fl LysM cre conditional knock-out (KO) mice showed an increased tumor burden and increased mortality in this model of inflammation driven CAC. Isolated myeloid cells from these mice exhibited an up-regulation of M2-marker genes and a down-regulation of pro-inflammatory cytokines. Moreover we found an increase in immune-regulatory innate cells of the secondary lymphoid organs. T-cells isolated from PTEN KO-mice had decreased cytokine production as well as a reduced proliferative potential ex vivo. Therefore we suggest that myeloid PTEN deficiency leads to reduced T-cell stimulation thereby promoting intestinal tumor growth.
Taken together this study highlights the importance of the PI3K/PTEN signaling axis in myeloid cells to control tumor immune surveillance and supports the idea that PI3K inhibitors currently used in clinical settings may have additional functions beyond tumor cell targeting.
Citation Format: Mario Kuttke, Julia Pisoni, Emine Sahin, Sophie Percig, Andrea Vogel, Daniel Kraemmer, Leslie Hanzl, Johannes Schmid, Gernot Schabbauer. PTEN-deficiency in myeloid cells alters tumor immune surveillance in a murine model of inflammation driven colon cancer. [abstract]. In: Proceedings of the AACR Special Conference: Tumor Immunology and Immunotherapy: A New Chapter; December 1-4, 2014; Orlando, FL. Philadelphia (PA): AACR; Cancer Immunol Res 2015;3(10 Suppl):Abstract nr B74.
- ©2015 American Association for Cancer Research.