Chronic inflammation and cancer: suppressing the suppressors

Abstract

Chronic inflammation typical to various chronic diseases is associated with immunosuppression, mediated primarily by immature myeloid-derived suppressor cells (MDSCs). A variety of factors induce MDSC differentiation arrest, thus manipulating the host's immune function and suppressing the innate and adaptive immune systems, as reflected by their impaired status associated with down-regulated expression of the CD247 molecule. Such chronic inflammation-induced immunosuppressive features are also found in many tumors, generating tumor micro- and macro-environments that act as critical barriers to effective anti-tumor responses and therapies. This knowledge offers new and novel candidate immune targets for therapeutic interventions, in combination with more conventional approaches as chemotherapy, radiotherapy, and cancer cell targeted therapy. Therapeutic manipulation of chronic inflammation during cancer development is likely to enhance efficacy of treatments such as vaccinations, and adoptive T cell transfer, thus switching the chronic pro-cancer inflammatory environments into an anti-cancer milieu. Based on the functional relevance of immune networking in tumors, it is advantageous to merge monitoring immune biomarkers into the traditional patient's categorization and treatment regiments, which will provide new prognostic and/or predictive tools to clinical practice. A better identification of environmental and tumor-specific inflammatory mechanisms will allow directing the clinical management of cancer toward a more personalized medicine.

Fig. 1

Common features of chronic inflammation-induced immunosuppression. The link between the pathology-free chronic inflammation model we used in the course of our studies and the various pathologies characterized by chronic inflammation as cancer, infectious, and autoimmune diseases is the generation of a suppressive milieu, in which MDSCs play a crucial role in manipulating the micro- and macro-environments. The expansion and activation of MDSCs lead to an increased production of pro-inflammatory mediators and suppressive compounds such as NO⁻ and ROS. The outcome of such a newly generated inflammatory environment is a general suppression of both adaptive and innate immune cells that enables the pathology progression

Fig. 2

TNF-α is a master regulator of MDSCs during chronic inflammation. By signaling through TNFR-2, TNF-α promotes MDSC survival via up-regulation of the anti-apoptotic FLICE-inhibitory protein (c-FLIP), which inhibits activation of apoptotic caspase-8. Moreover, TNF-α also controls MDSC differentiation and activation. The differentiation of MDSCs to non-suppressive myeloid cells such as macrophages (MΦ) and dendritic cells (DCs) is inhibited by TNF-α by up-regulating the expression of both the S100A8/9 pro-inflammatory proteins and their corresponding receptor RAGE. In parallel, TNF-α also controls the ability to produce suppressive compounds such as urea, NO⁻, and ROS. Taken together, these alterations manifested by TNF-α lead to in vivo inhibition of immune functions

Fig. 3

The obstacles in obtaining a successful treatment. The important role of the immune system in eliminating cancer is unquestionable. The effective function of the immune system in conjunction with various standard treatments given today to cancer patients is critical, due to the immune system “responsibility” to eliminate cancer cells that fail to be destroyed by the conventional therapies. An effective therapy against cancer should take into consideration not only the tumor itself, but also its unique environment that protects it from complete eradication and should include five important parameters: (a) Elimination of the tumor cells, leading to immunogenic death; (b) Blockade/destruction of the suppressive cells, (c) Activation of effector immune cells, (d) Neutralization of pro-tumorigenic factors, and (e) Inhibition of angiogenesis. These parameters must be routinely monitored prior to and following treatment in order to choose an optimal combinatorial therapy that will lead to a beneficial optimal personalized treatment