A class of immune suppressor cells termed myeloid-derived suppressor cells (MDSC) is known to be elevated in many solid tumor settings. MDSC are a heterogenous population of early myeloid cells that expand from the bone marrow during tumor progression and have the ability to inhibit both innate and adaptive immunity. Previous work from our laboratory and others indicated that patients with cancer exhibited reduced activation of signaling pathways when stimulated with Type I and II IFN as compared to normal donors. This reduced immune response could be a barrier to successful clinical outcomes, since ability to respond to IFN is known to be important for anti-tumor immunity and efficacy of immune-based therapies. We hypothesized that MDSC could inhibit an immune response to the growing tumor by reducing the ability of immune cells to respond to IFN stimulation. C26 tumor bearing mice had significantly elevated levels of GR1+/CD11b+ MDSC as compared to control mice, and splenocytes from these mice exhibited reduced phosphorylation of STAT1 in response to Type I and II IFN. Depletion of MDSC in C26 bearing mice restored splenocyte IFN responsiveness. Spleens from C26 tumor bearing animals displayed elevated levels of iNOS and nitric oxide (NO), which was associated with increased levels of nitration on STAT1. In vitro treatment of splenocytes with a nitric oxide donor led to a decreased STAT1 IFN response. Finally, splenocytes from tumor-bearing iNOS knockout mice exhibited a significantly elevated IFN-response as compared to WT tumor-bearing mice. This demonstrated a novel mechanism of MDSC inhibition and created a direct link between increased nitric oxide and reduced IFN responsiveness.
We further investigated an association between pro-inflammatory cytokines, subsets of MDSC, and reduced IFN responsiveness in patients with GI cancer. Plasma IL-6 was correlated with CD33+HLADR CD15+ MDSC, while IL 10 correlated with CD33+HLADR-CD15- MDSC. The percentage of multiple MDSC subsets were inversely correlated with IFN α-induced STAT1 phosphorylation in CD4+ T cells, while co-culture with in vitro generated MDSC led to reduced IFN α-responsiveness in both PBMC and the CD4+ T cells from normal donors. These data support our findings that MDSC reduce IFN responsiveness and demonstrate that this also occurs in patients with cancer.
We also hypothesized that psychological stress could lead to changes in factors that modulate MDSC. It was discovered that patients with high cancer-specific stress had significantly elevated salivary cortisol and IL-1RI levels. Interestingly, significantly increased MDSC levels were observed in patients with lower cancer-specific stress. Additional long-term stress analyses of the number of stressful events that affected these patients revealed that patients with more stress overall trended toward elevations in MDSC. This study indicated the existence of a complex relationship between stress and immune function in breast cancer patients.
Taken together, these data demonstrate a novel mechanism of MDSC action and provide evidence that environmental factors, such as psychological stress, can lead to alterations in MDSC in patients with cancer.