Myeloid-derived suppressor cells (MDSC) are a heterogeneous group of immature myeloid cells that can be induced under chronic inflammatory conditions, such as autoimmune diseases, chronic infection, or malignancies. MDSC are produced in the bone marrow and circulate in the peripheral blood to reach the tumor microenvironment (TME) where they can promote tumor growth and expansion via immune and non-immune mechanisms. MDSC suppress the immune system via increased production of L-arginase-1, indoleamine 2,3-dioxygenase, and immunomodulatory cytokines, such as IL-10, as well as increased expression of checkpoint molecules, such as PD-L1. Moreover, MDSC may facilitate tumor invasion and metastases by producing matrix metalloproteinases and angiogenic growth factors, such as vascular endothelial growth factor (VEGF) in the TME.
Several studies have shown that MDSC in blood or TME can be associated with prognosis and treatment outcomes. The inflammation in the TME can lead to the release of inflammatory cytokines by the tumor and immune cells, which can promote MDSC expansion. Moreover, tumor cells release microvesicles into the circulation, which contain biologically active molecules, such as nucleic acids and enzymes, which act as stimulatory signals for MDSC and lead to their expansion. Therefore, tumor invasiveness can be associated with the level and activity of MDSC in TME and possibly in the blood.1
In our study, we investigated the correlation between MDSC in peripheral blood prior to cystectomy with treatment outcomes in patients with non-metastatic urothelial carcinoma of the bladder. Our analyses demonstrated that the percentage of total MDSC and the polymorphonuclear subtype of MDSC in peripheral blood was significantly lower among patients who achieved pathologic complete response (pT0N0) after radical cystectomy (with neoadjuvant chemotherapy given in a subset of them). Moreover, patients with a lower percentage of MDSC in peripheral blood had significantly longer recurrence-free and overall survival.2 The correlation between MDSC and survival in this analysis warrants further validation in prospective studies to clarify the putative prognostic role of MDSC in patients with urothelial carcinoma of the bladder. Moreover, studies need to investigate the effect of the addition of MDSC-targeted therapies to immune checkpoint inhibitors. Last, but not least, measuring the MDSC in the peripheral blood can be a minimally-invasive and low-cost test that can be easily incorporated in clinical trials as an exploratory endpoint.
Written by: Jaleh Fallah, MD, and Moshe C. Ornstein, MD, Taussig Cancer Institute, Cleveland Clinic, Cleveland, Ohio (Twitters: @Jaleh_Fallah and @MosheOrnsteinMD); Petros Grivas, MD, PhD, Department of Medicine, Division of Oncology, University of Washington, Fred Hutchinson Cancer Research Center, Seattle Cancer Care Alliance, Seattle, Washington, Twitter: @PGrivasMDPhD
References:
1. Fleming, Viktor, Xiaoying Hu, Rebekka Weber, Vasyl Nagibin, Christopher Groth, Peter Altevogt, Jochen Utikal, and Viktor Umansky. "Targeting myeloid-derived suppressor cells to bypass tumor-induced immunosuppression." Frontiers in immunology 9 (2018): 398.
2. Fallah, Jaleh, Claudia Marcela Diaz-Montero, Patricia Rayman, Wei Wei, James H. Finke, Jin S. Kim, Paul G. Pavicic Jr et al. "Myeloid derived suppressor cells (MDSC) in non-metastatic urothelial carcinoma of bladder is associated with pathologic complete response (pCR) and overall survival." Clinical Genitourinary Cancer (2020).
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