Targeting of Myeloid Derived Suppressor Cells Using Anti-inflammatory and Pro-inflammatory Agents

C l i n M e d International Library Citation: Forghani P, Waller EK (2015) Targeting of Myeloid Derived Suppressor Cells Using Anti-inflammatory and Pro-inflammatory Agents. Int J Cancer Clin Res 2:028 Received: September 03, 2015: Accepted: October 01, 2015: Published: October 03, 2015 Copyright: © 2015 Forghani P. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. Forghani and Waller. Int J Cancer Clin Res 2015, 2:4

Association of inflammation with tumor progression through accumulation of MDSC has been resulted in inhibition of anti-tumor immunity and facilitating tumor growth [9,10].MDSCs are expanded in bone marrow and recruited into the blood, lymph nodes, and tumor microenvironment of experimental animals or patients with cancer to inhibit both adaptive and innate immunity [9,[11][12][13][14].In individuals with established cancer, MDSCs were introduced as a key factor in preventing the efficacy of immunotherapies [10,15].C), a pro-inflammatory agent decreased MDSCs in both blood and tumor, directly acting on MDSCs.Poly (I: C) stimulated MDSC exhibited a "matured" phenotype, based on increased CD80, CD86, and MHC II expression when compared to un-stimulated MDSC obtained from murine spleens.Poly (I: C) in the setting of breast cancer affects MDSC generation, differentiation and also targets cancer cells, consequently leading to reduction of MDSC numbers and lower MDSC suppressive function, and improving tumorspecific T-cell functions [51].

Combination therapy and adverse effects of known approaches
Current studies are focused on combination of MDSCs-based approaches with different forms of immunotherapy targeting the function and/or numbers of MDSCs as follows: i) Gemcitabine has been shown to reduce splenic MDSC levels in tumor bearing mice and combining gemcitabine with IFN-beta markedly enhanced antitumor efficacy in a HER-2/neu tumor model [52].ii) sunitinib therapy in combination with low-dose radiotherapy modestly improved survival in a mouse model of glioma [53].Of note, combined therapy with high dose radiation, resulted in fatal toxicities and limiting the feasibility of this combination [21,53].iii) Combining the TroVAax (MVA-5T4) vaccine with sunitinib, IL-2, or IFN-α in RCC patients (phase III trial), did not enhance survival relative to sunitinib alone (or IL-2 or IFN-α alone) [54].Some treatments that target MDSCs showed pleiotropic effects on other immune system components.Chemotherapeutic drugs that are commonly used to treat cancer not only affect the tumor but also the immune system, having a crucial impact on antitumor responses [55,56].5-fluorouracil (5-FU) is one of chemotherapy approaches, which selectively eliminated MDSC at low doses also showed strong negative effects on the immune system making immunotherapy ineffective [57].Another study showed that treatment with CPT11 or the 5FU + CPT11 combination accumulates MDSCs and produce elevated levels of NO and ROS that resulted in DNA damage during colorectal cancer [58,59].Also, using anti-Gr-1 mAb for depletion of MDSCs in mice [60,61] has been showed adverse effect on memory CD8 + T cells, γδT cells and mice plasmacytoid dendritic cells expressing GR-1 [62][63][64][65].Altogether, above reported toxic effects of these approaches must be considered in the future design of new combination therapies.

Summary
Taken together, it is mandatory to have novel strategies that target MDSCs and boost immune responses to achieve better efficiency of cancer immunotherapy.Given the critical role of MDSCs in suppressing T-cell activation and proliferation and regulation of cell mediated anti-tumor immunity, it is time to investigate the influence of drugs with both anti-and pro-inflammatory effects on MDSCs in the tumor microenvironment.The concept of modulation of MDSCSs through combining of anti-inflammatory and pro-inflammatory drugs may lead to the development of a potent anticancer therapy.and create an environment that suppressing anti-tumor immune responses.[15,34,35].During two last decades, accumulating evidence has indicated that chronic inflammation promotes tumor onset and development through different mechanisms such as the production of reactive oxygen species (ROS), production of vascular endothelial growth factor (VEGF) and production of matrix metalloproteases (MMP) s, which facilitate invasion and metastasis [34].Additionally, different studies have shown that pro-inflammatory cytokines IL-1β [36], IL-6 [17], GM-CSF, and G-CSF, which are found in the microenvironment of many tumors, significantly increase MDSC accumulation and suppress T cell activation and function [11,37,38].Furthermore, IL-1β induced inflammation, which aids MDSC and macrophage cross-talk, resulting in increasing MDSC mediated of immune suppression [11,39].

Contribution of chronic inflammation to tumor progression suggested by Rudolf Virchow
Because of the connection between inflammation and cancer, blocking inflammatory mediators regulating inflammation are expected to be effective in reducing tumor incidence and delaying tumor growth [7,19,40].Different strategies target MDSCs directly by changing their expansion, recruitment, phenotype and/or immunosuppressive activity [13].i) Non-steroidal anti-inflammatory drugs (NSAIDs), Cyclooxygenase-2 (COX-2) inhibitors target the COX-2 enzyme and suppress activation of MDSCs through CCL2, CXCL12, or PGE2 inhibition and increase cytotoxic T lymphocytes (CTLs) [41,42].ii) Peroxisome proliferator-activated receptor-γ (PPARγ) is an anti-inflammatory molecule expressed in the myeloidlineage [43].Dominant-negative PPARγ expression in myeloid cells reduces expansion of the CD11b + Ly6G + population [44].iii) Phosphodiesterase-5 (PDE-5) inhibitors including: sildenafil, tadalafil, and vardenafil are used for treatment of nonmalignant diseases.These drugs increase infiltration of activated CTLs into tumor and tumor-induced T cell through down-regulation of Arg 1 , iNOS, and IL-4α expression in MDSCs [40].VI) Bardoxolone methyl, also known as CDDO-Me or RTA 402, is a synthetic triterpenoid, which has anticancer and cancer-preventive activities.It has been shown to be a potent activator of the transcription factor NFR2, which up-regulates several antioxidant genes resulted in abrogation of immunosuppressive activities of MDSCs and restored immune responses in both preclinical murine model and patients with renal cell carcinoma [45,46].V) Silibinin, a natural flavonoid from the seeds of milk thistle, has been used as an anti-inflammatory agent to reduce the toxicity of cancer chemotherapy [47].Our findings in an advanced tumor model of breast (4T1) showed that the decrease in tumor growth and MDSC accumulation in the blood of silibinintreated tumor-bearing animals is not primarily due to a direct antitumor effect on 4T1 cells or suppression of MDSC development in bone marrow, but rather represents an indirect effect of silibinin on T-cells in the tumor microenvironment.Also silibinin treatment resulted in immune polarization to a M1 phenotype in the tumor microenvironment.Our data also indicate that silibinin decreases MDSC in a chemokine (CCR2) dependent manner that provide a mechanism for the decreased accumulation of MDSC in the tumor and a decrease in tumor-associated immunosuppression [48].
In contrast to anti-inflammatory mediators, there are a few reports for effects of pro-inflammatory mediators on MDSCs.For example: i) S100A8/A9 proteins induce MDSCs accumulation, therefore, and in vivo blocking of S100A8/A9 binding, reduces, but does not eliminate MDSC accumulation in tumor-bearing mice [38].ii) Tumor necrosis factor-α (TNF-α) blocks myeloid cell differentiation and augment the suppressive activity of MDSCs in chronic inflammatory settings.Administration of a TNF-α antagonist (etanercept) reduces MDSCs' suppressive activity and promotes their maturation into dendritic cells and macrophages [19,49].While heightened levels of proinflammatory mediators or adoptive transfer of inflammatory cells increases tumor development [50], we have shown that iii) Poly (I: So far, several approaches have been suggested to modulate MDSCs via different mechanisms including: inhibition of tumorderived factors, suppression of generation and/or expansion of • Page 2 of 4 • ISSN: 2378-3419 Forghani and Waller.Int J Cancer Clin Res 2015, 2:4