UCLA

The role of immune signaling in cancer is complex and conflicting. Inflammatory signaling can drive an anti-tumor response, but copious evidence suggests that chronic inflammation also promotes tumorigenesis. The most well-characterized of inflammatory pathways is the Toll-like receptor (TLR) pathway, which promotes downstream NF-κB activation. Mutations in TLRs are associated with a higher risk of prostate cancer.

Using the TRAMP model of prostate cancer, we report the impact of TLR signaling

disruption on tumor growth and progression. The adaptor protein MyD88 is an essential

component of signaling for almost all TLRs, so loss of MyD88 abrogates most TLR signaling. Absence of MyD88-dependent signaling in TRAMP prostate tumors resulted in a more aggressive disease, as determined by histology. Analysis of infiltrating immune cells revealed an increase in CD11b+Gr-1+ MDSCs (myeloid-derived suppressor cells) in MyD88-/- tumors when compared to MyD88+/+ tumors, both in number and in functional output. MyD88-/- tumors also displayed increased expression of some chemokines involved in MDSC recruitment.

An explicit link between MyD88-dependent signaling and MDSC accumulation was suggested by the expression of S100A9, a chemokine and a TLR4 ligand. Specifically, this indicates that MyD88-dependent signaling may play a role within the MDSCs themselves. In vitro differentiation of MDSCs from bone marrow skewed towards the granulocytic subset (gMDSCs) in MyD88-/- cells, supporting an internal role for MyD88 signaling. MyD88-/- MDSCs also showed an increased sensitivity to chemotaxis mediated by S100A9 and an increase in Arg-1 expression following S100A9 stimulation. We conclude that MyD88-dependent signaling may play an essential role in regulating the population of tumor-infiltrating cells by reducing MDSC activity and MDSC response to S100A9-mediated chemotaxis, thus limiting prostate tumor progression.