Figure 1.

A proposed model of chronic inflammation progressing to tumor formation. A chronic insult such as autoimmunity or infection leads to a steady inflamed tissue state. Tumor-associated macrophages (TAM) of the M1 variety begin to produce cytokines that promote Th17 cell differentiation from naïve CD4⁺ T lymphocytes such as IL-6, IL-23, IL-1β and TNF-α. One of the key cytokines produced by M2 TAM is TGF-β, which may further encourage Th17 development. Myeloid-derived suppressor cells serve an immunosuppressive role within the microenvironment by producing TGF-β as well as other regulatory factors, but may also encourage further Th17 differentiation by secreting IL-6. The production of TGF-β would likely also have the effect of inducing CD4⁺Foxp3⁺Tregs within the tumor microenvironment while also suppressing inflammatory cytokine production from the TAM themselves. However, these combined suppressive signals may not be sufficient to overcome the self-perpetuating cycle of activation established between Th17 cells and TAM. At the same time, this suppressive environment may greatly hamper, or even eliminate, the possibility for Th1 and CD8⁺ T cells to mount an immune response. The net effect of these cellular interactions within the tumor microenvironment is to limit anti-tumor immunity from Th1 and CD8 T cells while continuing to encourage chronic inflammation, angiogenesis, and overall cancer cell survival and proliferation.