Granulopoietic Growth Factor Secretion in Ovarian Carcinoma as a Mechanism for the Emergence of Immune Suppressive Myeloid Subsets
Abstract
A major problem facing effective ovarian cancer immunotherapy is the capacity of malignant populations to inhibit immune activation or evade destruction. Among prominent mechanisms thought to impede the anticancer response is the accumulation of pro-tumorigenic myeloid populations, termed myeloid-derived suppressor cells (MDSC). However, there is a fundamental gap in knowledge regarding the exact mechanisms that drive their development or accumulation. To that end, we originally hypothesized that the overproduction of granulocyte-colony stimulating factor (G-CSF) in ovarian carcinoma facilitates MDSC accumulation. However, during the course of these studies, we discovered that the levels of IL-8 overwhelmed all other cytokines/chemokines tested, including G-CSF. Consequently, we refined our original hypothesis to reflect tumor-derived IL-8, in lieu of G-CSF as a major component of MDSC-mediated ovarian tumor progression. Thus far, our data have led to the: 1) identification of distinct MDSC subsets in ovarian cancer patients; 2) identification of several pro-inflammatory cytokines in matched patient sera, notably IL-8; 3) development of a xenograft model that recapitulates the MDSC and IL-8 phenotype seen in patient samples; and 4) observation that IL-8 knockdown in ovarian cancer cell line models significantly improves overall survival. Altogether, this new axis in myeloid-ovarian tumor biology has important implications for IL-8-based clinical interventions.
Document Details
- Document Type
- Technical Report
- Publication Date
- Jun 01, 2012
- Accession Number
- ADA563781
Entities
People
- Scott I Abrams
Organizations
- Health Research, Incorporated