Abstract P4-04-06: Young women's breast cancer is characterized by increased immune suppression through circulating myeloid derived supressor cells
Authors: Borges VF , Ramirez O , Borakove M , Manthey E , Diamond JR , Elias AD , Finlayson C , Kounalakis N , Jordan K 
Published: August 2014

Background: Women age 20–40 have a higher ten-year risk for developing breast cancer than the five other leading cancers in this gender and age group combined. Women currently in their 30s have a 1/203 chance of developing breast cancer over the next ten years. Moreover, cancers diagnosed in younger women have a signficantly higher risk of death for reasons that are not fully identified. Myeloid derived suppressor cells (MDSC) have a role in suppressing anti-tumor immunity through Jak/Stat pathway activation by generation of reactive oxygen species (ROS) and arginase-1, and correlate preclinically with cancer progression and in human canceres with poorer prognositic features and outcomes. Our Young Women's Breast Cancer Translational Program seeks to identify immunologic differences potentially contributing to the poorer prognosis and potential targets for development of immunomodulatory treatment.

Hypothesis: We hypothesized that newly diagnosed, treatment-naive young breast cancer cases would have higher percentage of circulating MDSC with T cell suppressive function than similar age women without breast cancer.

Methods: We conducted IRB approved, prospective translational studies of women age 40 and under both affected and unaffected by breast cancer. Exclusion criteria included pregnancy, known autoimmunity or immunosuppressive medications, or other cancers. MDSC were isolated from peripheral blood and phenotyped through standard protocols. T cell suppressive abilites were tested in coculture assays for expression of activation markers CD25 and CD69, and production of gamma-interferon. Identification of mechanism of suppression was assayed through secretion of arginase-1and generation of ROS.

Results: No difference in percentage of MDSC was identified between young women with breast cancer (n = 61) and unaffected subjects (n = 18). However, a statistically significant increase in the MDSC ability to suppress T cell activation was identified in the breast cancer cohort with diminished CD25 and CD69 expression and diminished production of gamma-interferon. MDSC from young breast cancer subjects secreted significantly more arginase-1 from MDSC. No significant difference in generation of ROS was found between the two cohorts.

Conclusions: The presence of equal rather than higher numbers of circulating MDSCs between the young breast cancer versus unaffected subjects was unexpected in comparison to prior publications on MDSC in cancer. Our results may differ due to our larger sample size or the alignment by gender and age the cohorts being more representative. Also, these are the first data on MDSC in a young female population. Despite equal numbers of MDSCs, the functional analyses demonstrate MDSC isolated from breast cancer have enhanced T cell suppression capabilities compared with normal controls. These data provacatively suggest a functional difference inherent to MDSC in the young breast cancer-bearing host. Moreover, they indicate that normal young women have realtively high levels of MDSC that are available for cancer to ursurp and induce immune suppression. Identification of secretion of arginine-1 as a potential mechanism of immune supporession in young women's breast cancer warrants further investigation.

Citation Information: Cancer Res 2012;72(24 Suppl):Abstract nr P4-04-06.