KRAS-Induced GM-CSF Promotes Immune Evasion in PDA

Pancreatic ductal adenocarcinomas (PDA) are highly aggressive, lethal cancers characterized by frequent KRAS mutations and a dense, fibrous stroma in which a high accumulation of inflammatory cells is thought to create an immunosuppressive environment. However, the mechanisms by which PDAs remodel the stromal environment in order to evade immune detection are unclear. Bayne and colleagues noted that murine PDAs induced by mutation of Kras and p53 are highly infiltrated by Gr-1⁺ CD11b⁺ myeloid-derived suppressor cells (MDSC) capable of inhibiting CD8⁺ T-cell proliferation and activity in vitro. High levels of granulocyte-macrophage colony-stimulating factor (GM-CSF) were secreted by every murine PDA cell line tested compared with normal pancreatic ductal cell lines, implicating this cytokine as a tumor-derived soluble factor responsible for the recruitment of immunosuppressive Gr-1⁺ CD11b⁺ cells to PDAs. Indeed, antibody-mediated neutralization of GM-CSF abrogated the generation of Gr-1⁺ CD11b⁺ cells and led to CD8⁺ T-cell–dependent rejection of PDA xenografts. Pylayeva-Gupta and colleagues came to the same conclusions in their efforts to understand modulation of the host immune response by KRAS during PDA development by injecting Kras-mutant primary ductal epithelial cells into the pancreata of recipient mice. Additionally, these authors showed that the accumulation of Gr-1⁺ CD11b⁺ cells was associated with a tumor-cell specific increase in the transcription of GM-CSF that was dependent on KRAS activation and could be inhibited by pharmacologic inhibition of downstream effectors of KRAS such as PI3K or MEK. Importantly, the clinical relevance of these findings was highlighted by both groups' observation of significantly higher levels of GM-CSF in human PDAs compared with adjacent normal pancreatic tissue. Disruption of the cross-talk between tumor-derived GM-CSF and Gr-1⁺ CD11b⁺ MDSCs may therefore be an effective immunotherapeutic strategy for treatment of PDA.

Bayne LJ, Beatty GL, Jhala N, Clark CE, Rhim AD, Stanger BZ, et al. Tumor-derived granulocyte-macrophage colony-stimulating factor regulates myeloid inflammation and T cell immunity in pancreatic cancer. Cancer Cell 2012;21:822–35.

Pylayeva-Gupta Y, Lee KE, Hajdu CH, Miller G, Bar-Sagi D. Oncogenic Kras-induced GM-CSF production promotes the development of pancreatic neoplasia. Cancer Cell 2012;21:836–47.