Hypothetical model for the role of cytokines in the process of peripheral tumor development in GzmB-Tax transgenic mice. This model would suggest that there is a need for an initial injury to peripheral skin tissue (eg, ear puncture, tail clipping, and fighting). This injury would subsequently start an inflammatory response by skin epithelial cells (eg, keratinocytes [KC]) that release inflammatory cytokines such as IL-1α and IL-1β. These inflammatory cytokines could then act on ECs of nearby vessels to cause the extravasation of circulating LGLs and neutrophils (PMN) by upregulating adhesion molecules such as ICAM-1 and VCAM-1 on ECs. Circulating LGLs also constitutively express adhesion molecules on their surface (LFA-1 and VLA-4), which promote their binding to activated ECs and extravasation. Once at the site of inflammation, these LGLs would become activated and release cytokines such as GM-CSF, which could then cause a systemic increase in PMN production and PMN extravasation into the tumors. In addition, these LGLs produce large quantities of IFNγ that could potentially initiate/exacerbate this inflammatory process by upregulating the expression of adhesion molecules such as ICAM-1 and VCAM-1 at this peripheral site.