Paving the Road to Tumor Development and Spreading: Myeloid-Derived Suppressor Cells are Ruling the Fate

Abstract

Cancer development is dependent on intrinsic cellular changes as well as inflammatory factors in the tumor macro and microenvironment. The inflammatory milieu nourishes the tumor and contributes to cancer progression. Numerous studies, including ours, have demonstrated that the tumor microenvironment is immunosuppressive, impairing the anticancer immune responses. Chronic inflammation was identified as the key process responsible for this immunosuppression via induction of immature myeloid-derived suppressor cells (MDSCs). Upon a prolonged immune response, MDSCs are polarized toward immunosuppressive cells meant to control the exacerbated immune response. In cancer, the chronic inflammatory response renders the MDSCs harmful. Polarized MDSCs suppress T-cells and natural killer cells, as well as antigen-presenting cells, abrogating the beneficial immune response. These changes in the immunological milieu could also lead to high frequency of mutations, enhanced cancer cell stemness, and angiogenesis, directly supporting tumor initiation, growth, and spreading. The presence of MDSCs in cancer poses a serious obstacle in a variety of immune-based therapies, which rely on the stimulation of antitumor immune responses. Cumulative data, including our own, suggest that the selection of an appropriate and effective anticancer therapy must take into consideration the host's immune status as well as tumor-related parameters. Merging biomarkers for immune monitoring into the traditional patient's categorization and follow-up can provide new predictive and diagnostic tools to the clinical practice. Chronic inflammation and MDSCs could serve as novel targets for therapeutic interventions, which can be combined with conventional cancer treatments such as chemotherapy, radiotherapy, and cancer cell-targeted and immune-based therapies. Intervention in environmental and tumor-specific inflammatory mechanisms will allow better clinical management of cancer toward more efficient treatment.

Keywords: MDSC; biomarkers; cancer; chemotherapy; immune monitoring; immunosuppression; immunotherapy; inflammation.

Figure 1

A vicious cycle of chronic inflammation and cancer is maintained by MDSCs. Cancer and chronic inflammation mutually support one another in multiple ways. The cycle begins with a chronic inflammatory response generated by any persistent insult, including cancer. The effector cell milieu is recruited and activated by DAMPs derived from the immunogenic insult and produces various proinflammatory signals (such as IL-1, IL-6, GM-CSF, TNF-α, IFNγ, VEGF, and PGE₂) (A). The proinflammatory signals persist and induce polarization and accumulation of MDSCs, which transform the beneficial inflammatory response to deleterious chronic inflammation. The MDSCs create a positive loop, increasing their own polarization and expansion by production of TNF-α and S100A8/9 proteins (B). The oxidative stress created by the production of NO and ROS by the MDSCs in the inflammatory sites may cause DNA damage and somatic mutations, increasing the risk for tumor initiation (C). MDSCs directly support tumor progression by increasing angiogenesis, tumor cell stemness, and metastasis (D). The suppressive activity of MDSCs inhibits the effector function of T-, NK-, and dendritic cells, abrogating the antitumor beneficial response (E). MDSCs further suppress the immune response by inducing Tregs, which can also directly support tumor growth by producing RANKL (F). The deleterious inflammatory milieu and the tumor itself provide more proinflammatory factors, further enhancing MDSC accumulation. Moreover, necrosis at the tumor releases endogenous DAMPs, which could either start the cycle of chronic inflammation and MDSC accumulation or keep perpetuating it (A,G).

Figure 2

Clinical implications of immune monitoring in cancer patients. Monitoring of patient’s immune status in a blood sample may provide invaluable insight and help design better treatment regimens. The level of circulating MDSCs indicates how suppressive the environment is, while the expression of CD247 in circulating T-cells senses the suppression directly. Patients who have low MDSCs and high CD247 expression have a better prognosis and are more likely to respond to treatment (competent), as there are less MDSCs to support the tumor’s growth and the immune system is functional (lower part). On the other hand, high MDSC levels and low CD247 expression indicate a suppressive protumorigenic environment and immunosuppression (upper part), providing a poor prognosis (non-competent). Immune monitoring can be used when choosing a chemotherapeutic drug for treatment (right panel). Drugs such as cyclophosphamide and irinotecan induce MDSC accumulation and generate a harmful suppressive environment, while 5FU and oxaliplatin alleviate the harmful settings. Low MDSCs and high CD247 indicate immune competence making the patient a good candidate for immune-based therapy, while in suppressed and non-competent patients immune-based therapy is likely to fail. Suppressed patients may benefit from anti-MDSC treatment (left panel): MDSC elimination with chemotherapy (gemcitabine and 5FU); induction of differentiation (ATRA); blocking the signals leading to MDSC accumulation (etanercept-blocking TNF-α, anti-GM-CSF, Avastin-blocking VEGF, specific tyrosine kinase inhibitor-CSF-1R inhibitor, and Celecoxib-COX-2 inhibitor); and inhibition of MDSC activity (nitroaspirin-blocking ARG-1/iNOS and sildenafil-blocking PDE-5). Success of anti-MDSC treatment could be measured by immune monitoring, as MDSC levels drop and CD247 expression recovers, making the patient immune competent and suitable for immune-based therapy.