Accumulated evidence has indicated that chronic and unresolved inflammation may play a critical role in the initiation, development, growth, and metastasis of cancer. The net outcome of the battle between the anti-tumor and the tumor promoting immune cells and their associated cytokines within the tumor environment will determine the ultimate fate of the affected tumors. Thus, understanding the interactions and mutual regulation of these complex immune networks within the tumor environment, rather than the role of individual components, is much more likely to guide us towards developing effective and specific cancer therapeutics. It is generally believed that CD4+ Th1 and CD8+ T cells comprise the primary force of immune cells responsible for inhibiting tumor growth and development, while TAM, MDSC, Cd4+Foxp3+Treg cells and Th17 cells and their associated cytokines IL-6, TNF, IL-1β, IL-23 and TGF-β may play important roles in promoting the growth and survival of cancer. However, it is difficult to draw a distinction and establish clear “black and white” classifications for which cell types are always pro-tumor or always anti-tumor.
Of particularly complexity is the immunoregulatory cytokine TGF-β. It has been long known that most tumor cells produce large amounts of TGF-β. Macrophages are a major cellular source of TGF-β during normal immune system responses. However, surprisingly, it is less known whether and how TGF-β functions in the cross-talk between TAM and cancer cells. In terms of the direct relationship between tumor cells and TGF-β, as well as the potential role TGF-β plays in determining T cell differentiation fate within developing and established tumors, many outstanding questions remain to be answered. For example, what is the effect of TGF-β on TAM within the tumor environment? Does TGF-β influence the production of proinflammatory cytokines IL-6, TNF and TGF-β in TAM? Of further importance is understanding whether TGF-β production, by either TAM, MDSC or cancer cells, preferentially induces CD4+Foxp3+ regulatory T cells, or instead promotes the development of Th17 cells within the microenvironment of tumors. The ultimate outcome of TGF-β's effects on tumor development and survival will most probably depend upon the balance of its activity at the interface between the cancer cells and the tumor associated immune cells. Further research into better understanding this balance at all stages of carcinogenesis is essential for the development of effective cancer therapies that target or utilize immunological mechanisms.
A similar paradox exists in determining the role of CD4+ Foxp3+ Tregs in tumor development, which is further complicated and particularly important given the control TGF-β has over Treg induction. With chronic infection or autoimmunity, CD4+ Treg cells help to limit inflammation and may hinder carcinogenesis by limiting cellular damage and inhibiting cycles of proliferation. Once a tumor is established, however, Tregs and their produced cytokines may instead play a role in promoting tumor survival by inhibiting cancer cell destruction. It is reasonable to assume that effector immune T cells could infiltrate into tumors and counter the growth and progression of cancer cells. However, to what extent Tregs may influence the effector T cell population within the tumor microenvironment remains unclear. Further unknown is what role Th1 and CD8+ T cells have on influencing both the local cytokine profile within the microenvironment as well as what influence these effector T cells have on TAM activity in either developing or established solid tumors. Given the recognized tumor promoting function of macrophages and their inflammatory cytokines, the potential effects of these anti-tumor immune Th1 and CD8+ T cells on TAM over the course of tumor development are desperately needed.
Our belief is that the tumor-associated macrophages and oncogenic inflammation are regulated at multiple levels by T cell subsets, immunoregulatory cytokines, and also intracellular transcription factors such as NF-κB and STAT3. The net outcome of these complex regulations determines whether or not tumor cells grow, recur, and intrude, and thereby have an impact on the eventual survival of patients with cancer. While Treg cells and their cytokines likely serve to promote cancer cell growth and survival in established tumors, these same immunosuppressive properties also prevent autoimmunity and early stage cancer development. Even within established tumors immunoregulatory cytokines, such as TGF-β and IL-10, play potentially opposing roles in both promoting and discouraging cancer cell survival and a more thorough understanding of their effect in relation to the plethora of other cytokines and immune cells within the tumor microenvironment is needed. Th17 cells may play a key role in providing a constant proinflammatory environment within established tumors while also influencing cell fate decisions and activation. Chronic infection and inflammation could provide the priming to encourage initial carcinogenesis, and, whilst establishing, TAM and MDSC cells may heavily encourage Th17 cell development and proliferation through the production of TGF-β and IL-6 cytokines. A proposed model outlining how this cycle of inflammation may perpetuate and lead to cancer development and survival can be found in Figure .
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 (more ...)
Once initially established, Th17 cells may then create a chronic environment of inflammatory factors that further activates TAM and self-propagates, encouraging angiogenesis and cancer cell survival through STAT3 activation and anti-apoptotic protein production. The immunosuppressive effects of Tregs within the tumor microenvironment may prevent initiation of antitumor immune responses by IFN-γ producing CD4+ Th1 cells and CD8+ T cells, but may not be sufficient to overcome the already established cycle of IL-6 and STAT3-mediated inflammation. There remains much to be learned of the interactions between these various cell types within the tumor microenvironment. However, teasing apart and understanding these mechanisms is essential to finding an effective therapeutic approach for altering pro-tumor immune signaling while also limiting potential side-effects for the patient.