Proteomic Pathway Analysis Reveals Inflammation Increases Myeloid-Derived Suppressor Cell Resistance to Apoptosis

Abstract

Myeloid-derived suppressor cells (MDSC) accumulate in patients and animals with cancer where they mediate systemic immune suppression and obstruct immunebased cancer therapies. We have previously demonstrated that inflammation, which frequently accompanies tumor onset and progression, increases the rate of accumulation and the suppressive potency of MDSC. To determine how inflammation enhances MDSC levels and activity we used mass spectrometry to identify proteins produced by MDSC induced in highly inflammatory settings. Proteomic pathway analysis identified the Fas pathway and caspase network proteins, leading us to hypothesize that inflammation enhances MDSC accumulation by increasing MDSC resistance to Fas-mediated apoptosis. Immunotherapies aimed at activating the host's immune system are promising strategies for the treatment of cancer because of their potential for minimal toxicity to healthy cells and their ability to induce immune memory that may protect against metastatic disease (1). Disappointingly, clinical trials of most cancer vaccines or other active T-cell mediated immunotherapies have not yielded significant patient responses (2). Because most cancer patients are immune suppressed, these failures are most likely because of the inability of cancer patients to immunologically respond to the immunotherapy agents. Although multiple mechanisms contribute to immune suppression in individuals with cancer (3), myeloid-derived suppressor cells (MDSC) 1 accumulate in virtually all cancer patients and are a major cause of tumor-induced immune suppression because of their inhibition of both adaptive and innate immunity (4). Because of their widespread presence and potent immune suppressive effects, identifying the cellular and molecular mechanisms responsible for MDSC accumulation and suppressive activity may facilitate the development of effective immunotherapy strategies.Chronic inflammation frequently precedes tumor onset (5) and many cancer cells produce pro-inflammatory mediators, suggesting that chronic inflammation contributes to tumorigenesis and tumor progression (6). We and others have previously demonstrated that inflammation via the proinflammatory molecules interleukin (IL)-1␤ (7, 8), toll-like receptor 4 (TLR4) (9), IL-6 (10), prostaglandin E2 (11, 12), and S100A8/A9 proteins (13, 14) increases either the number or the suppressive potency of MDSC, or both. This causative relationship between inflammation and MDSC induction led us to hypothesize that MDSC not only are an obstacle to immunotherapy, but also contribute to the onset and progression of tumors by inhibiting immune surveillance of newly transformed cells and by blocking natural immunity to established tumors (15).We are studying the effects of inflammation on tumor progression and MDSC development using the mouse BALB/cderived, spontaneously metastatic 4T1 mammary carcinoma (16) transfected with the IL-1␤ gene (4T1/IL-1␤) (7). When 1 The abbreviations used are: MDSC, myeloid-derived suppressor cells; DAPI, 4Ј,6-diamidino-2-phenylin...

Granulocytic myeloid-derived suppressor cells are cryosensitive and their frequency does not correlate with serum concentrations of colony-stimulating factors in head and neck cancer

“…13,20,28 Thus, we would like to propose that induced serum concentrations of CXCL8 mediate delayed apoptosis and increased mobilization from bone-marrow (possibly linked to a block in maturation) finally resulting in the accumulation of G-MDSC. 29 Certainly, future studies, which should use subsets of MDSC isolated directly from fresh, non-cryopreserved blood samples, are needed to further unravel the complex differentiation, mobilization and activation of these cells in human cancer patients. …”

Differential Content of Proteins, mRNAs, and miRNAs Suggests that MDSC and Their Exosomes May Mediate Distinct Immune Suppressive Functions

“…Interestingly, it has been previously reported that MDSC are able to resist Fas-mediated apoptosis under heightened inflammation. 60 Hence, if these exosomal miRNAs were delivered to MSDCs, they could contribute to the observed MDSC extended half-life by repressing Fas expression.…”

Myeloid-Derived Suppressor Cell Survival and Function Are Regulated by the Transcription Factor Nrf2

“…Cells were stained with antibodies, with Annexin V and PI, or with DCFDA as described (43, 44). Samples were analyzed on a Beckman/Coulter Cyan ADP flow cytometer using Summit software.…”