Myeloid-derived Suppressor Cells Adhere to Physiologic STAT3- vs STAT5-dependent Hematopoietic Programming, Establishing Diverse Tumor-Mediated Mechanisms of Immunologic Escape

Abstract

The receptor tyrosine kinase inhibitor, sunitinib, is astonishingly effective in its capacity to reduce MDSCs in peripheral tissues such as blood (human) and spleen (mouse), restoring responsiveness of bystander T lymphocytes to TcR stimulation. Sunitinib blocks proliferation of undifferentiated MDSCs and decreases survival of more differentiated neutrophilic MDSC (n-MDSC) progeny. Ironically, sunitinib’s profound effects are observed even in a total absence of detectable anti-tumor therapeutic response. This is best explained by the presence of disparate MDSC-conditioning stimuli within individual body compartments, allowing sensitivity and resistance to sunitinib to coexist within the same mouse or patient. The presence or absence of GM-CSF is likely the major determinant in each compartment, given that GM-CSF’s capacity to preempt STAT3-dependent with dominant STAT5-dependent hematopoietic programming confers sunitinib resistance and redirects differentiation from the n-MDSC lineage to the more versatile monocytoid (m-MDSC) lineage. The clinical sunitinib experience underscores that strategies for MDSC and Treg depletions must be mindful of disparities among body compartments to avoid sanctuary effects. Ironically, m-MDSCs manifesting resistance to sunitinib also have the greatest potential to differentiate into tumoricidal accessory cells, by virtue of their capacity to respond to T cell-secreted IFN-γ or to TLR agonists with nitric oxide and peroxynitrate production.

The Role of Inflammation in Kidney Cancer

“…MDSC express enzymes (e.g., arginase 1) that can deplete select amino acids in the tumor microenvironment (L-arginine and L-cysteine), thereby limiting the availability of these amino acid which are necessary for lymphocyte activation (13) (Srivastava et al 2010). Some MDSC produce reactive oxygen species (ROS) and/or inducible nitric oxide synthase, resulting in reduced CTL activity and IFN-γ production (Corzo et al 2009;Kusmartsev et al 2008;Cohen et al 2012;Ko et al 2010). MDSC indirectly inhibit T cell immunity by stimulating expansion of regulatory T cells (Treg) (Huang et al 2006;Pan et al 2010).…”

Modification of the Tumor Microenvironment as a Novel Target of Renal Cell Carcinoma Therapeutics

“…Coincidentally, the promiscuous rTKI which have proved effective against human RCC also have profound impacts upon the immune system (8,9). For example, the promiscuous rTKI sunitinib causes pronounced depletion of peripheral blood myeloid-derived suppressor cells (MDSC), thereby restoring normal T cell function within that compartment.…”

“…For example, the promiscuous rTKI sunitinib causes pronounced depletion of peripheral blood myeloid-derived suppressor cells (MDSC), thereby restoring normal T cell function within that compartment. The even more promiscuous rTKI sorafenib similarly depletes peripheral MDSC, but also itself interferes with normal T cell function (9). While it is tempting to use these observations to explain sunitinib's therapeutic superiority to sorafenib in RCC, it is futile, because even RCC patients whose tumors progress rapidly during sunitinib therapy display dramatic MDSC depletion and normalized T cell function within their peripheral blood (9,10, 25).…”

Letter from the Editor

“…In addition, several manuscripts focusing on IL-1 (Ban et al, 2012, Cruz-Robles et al, 2009Latella et al, 2009;Rafferty et al, 2010),TH 2 cells (Durrant & Metzger, 2010;Zoghi et al, 2011), and Toll-like receptors (Cohen et al, 2012, Cordeau et al, 2012, Jha et al, 2011Negrini et al, 2013), which are some of the players of this immune interaction have been published recently in Immunological Investigations, and these authors may be well served to be alerted to the interaction that these molecules and cells have with bone growth and resorption.…”

“…Immune suppression: The hallmark of myeloid derived suppressor cells (Haile et al, 2012); PGE(2)-driven induction and maintenance of cancer-associated myeloidderived suppressor cells (Obermajer et al, 2012); Myeloid-derived suppressor cells adhere to physiologic STAT3-vs STAT5-dependent hematopoietic programming, establishing diverse tumor-mediated mechanisms of immunologic escape (Cohen et al, 2012); Myeloid-derived suppressor cells and anti-tumor T cells: A complex relationship (Monu & Frey, 2012); Highlights on molecular mechanisms of MDSCmediated immune suppression: Paving the way for new working hypotheses (Solito et al, 2012); Phenotypic plasticity of MDSC in cancers (Manjili, 2012); Indoleamine 2,3-dioxygenase and dendritic cell tolerogenicity (Harden & Egilmez, 2012); Myeloid-derived suppressor cells (MDSCs) in gliomas and glioma-development (Kohanbash & Okada, 2012); Saccharomyces as a vaccine against systemic Candidiasis (Liu et al, 2012).…”