Combined focal radiation and anti-mCTLA-4 antibody therapy modulates myeloid subset phospho-stat3 levels in the 4T1 tumor microenvironment, and results in tumor growth inhibition
David W Draper, Hillary Evens, Alden Wong, Scott Wise, and Maryland Rosenfeld Franklin
AACR Tumor Immunology and Immunotherapy
Introduction and Background
- Signaling through signal transducer and activator of transcription factor 3 (STAT3) in myeloid subsets triggers gene expression that has direct and indirect suppressive effects on several immune subsets.
- Selective targeting of STAT3 in myeloid cells has become an attractive therapeutic approach as it can prevent adverse effects that may otherwise be triggered by broad inhibition of the pathway.
- To facilitate development of drugs with selectivity for phospho-protein targets like STAT3, we have developed a phospho-flow panel that can measure phosphoprotein states in distinct myeloid subsets simultaneously.
- The 4T1 syngeneic breast cancer model was used due to its high prevalence of granulocytic (G) MDSCs, as well as other immunosuppressive myeloid subsets.
- Our results demonstrate that phospho-STAT3 (pSTAT3) levels were differentially regulated in MDSC and tumor-associated macrophage (TAM) subsets following in vivo treatment with focal radiation, anti-mCTLA-4, or the combination.