Tumor-induced immunosuppression plays a key role in tumor evasion of the immune system. A key cell population recognized as myeloid-derived suppressor cells (MDSC) contributes and helps orchestrate this immunosuppression.

SummaryNitric oxide (NO) is a major effector molecule in the destruction of tumor cells by activated macrophages. However, in many cases, developing neoplasms appear to be capable of impairing steps in the complex process leading to NO production as a means of avoiding immune destruction. After activation with lipopolysaccharide (LPS), peritoneal-ehcited macrophages (PEM) from mice bearing mammary tumors display alterations in their ability to lyse tumor cells due to reduced production of NO. In contrast, when these same cells are stimulated with LPS in combination with interferon ~/(IFN-~/), they are able to produce NO and lyse targets at normal levels. Since tumor-associated macrophages are intimately associated with the cells of the developing tumor, their ability to produce NO and lyse tumor targets is likely to be more relevant to controlling tumor growth. This population of macrophages exhibited a more profound inability to produce NO and lyse targets and, unlike the PEM, was not able to upregulate these functions even when treated with combinations of LPS and IFN-~. Northern and Western blots revealed that inducible nitric oxide synthase (iNOS) mRNA and protein levels correlated directly with the ability of each macrophage population to produce NO, and the levels of these macromolecules were altered sufficiently in tumor bearers' macrophages to account for the diminished NO production described. These results indicate that a spatial gradient of suppression of macrophage cytolytic activity and iNOS expression exists in mammary tumor-bearing mice, whereby macrophages from within the tumor exhibit a more pronounced suppression than the more distally located PEM. This suppression may be due to proximity of the macrophages to the developing tumor, macrophage maturational state, or both.

Background Adrenal tumors are commonly discovered on abdominal imaging. The majority of adrenal tumors are classified as “non-functional” and considered to pose no health risk, whereas a minority will be considered “functional” because they secrete hormones that increase risk for metabolic and cardiovascular diseases. Objective To evaluate the hypothesis that “non-functional” adrenal tumors (NFAT) increase risk for developing cardiometabolic outcomes when compared with having no adrenal tumor. Design Cohort study. Setting Integrated hospital system. Participants Exposed participants with benign NFAT (n=242) and unexposed participants with no adrenal tumor (n=1237). Measurements Medical records were reviewed from the time of abdominal imaging for development of incident outcomes (hypertension, composite diabetes [pre-diabetes or type 2 diabetes], hyperlipidemia, cardiovascular events, chronic kidney disease) (mean 7.7 years). Primary analyses evaluated independent associations between exposure status and incident outcomes using adjusted generalized linear models. Secondary analyses evaluated relationships between NFAT and cortisol physiology. Results NFAT were associated with significantly higher risk for incident composite diabetes when compared with no adrenal tumor (adjusted RR=1.87, 95% CI: 1.17, 2.98; absolute risk: 30/110 vs. 72/615, 15.6%). No significant associations between NFAT and other outcomes were observed. Higher “normal” post-dexamethasone cortisol levels (<1.8 mcg/dL) associated with larger NFAT size and a higher prevalence of type 2 diabetes. Limitations Potential bias in the selection of participants and ascertainment of outcomes. Conclusions Participants with NFAT had a significantly higher risk of developing diabetes when compared to participants without adrenal tumors. These results prompt a re-assessment of whether the classification of benign adrenal tumors as “non-functional” adequately reflects the continuum of hormone secretion and metabolic risk they may harbor.