Standardized Uptake Value for 18F-Fluorodeoxyglucose is a Marker of Inflammatory State and Immune Infiltrate in Cervical Cancer

Purpose: Chemo-radiotherapy for locally advanced cervical cancer fails in over a third of patients. Biomarkers with therapeutic implications are therefore needed. We investigated the relationship between an established prognostic marker, maximum standardized uptake value (SUVmax) on 18F-fluorodeoxyglucose positron emission tomography, and the inflammatory and immune state of cervical cancers. Experimental Design: An SUVmax most prognostic for freedom from progression (FFP) was identified and compared to known prognostic clinical variables in a cohort of 318 patients treated with definitive radiation with prospectively collected clinical data. Gene set enrichment analysis (GSEA) and CIBERSORT of whole transcriptome data from 68 patients were used to identify biological pathways and immune cell subpopulations associated with high SUVmax. Immunohistochemistry using a tissue microarray (TMA, N=82) was used to validate the CIBERSORT findings. The impact of macrophages on cervical cancer glucose metabolism was investigated in co-culture experiments. Results: SUVmax <11.4 was most prognostic for FFP (p=0.001). The GSEA showed that high SUVmax is associated with increased gene expression of inflammatory pathways, including JAK/STAT3 signaling. CIBERSORT and CD68 staining of the TMA showed high SUVmax tumors are characterized by a monocyte-predominant immune infiltrate. Co-culture of cervical cancer cells with macrophages or macrophage-conditioned media altered glucose uptake, and IL-6 and JAK/STAT3 signaling contribute to this effect. Conclusions: SUVmax is a prognostic marker in cervical cancer that is associated with activation of inflammatory pathways and tumor infiltration of myeloid-derived immune cells, particularly macrophages. Macrophages contribute to changes in cervical cancer glucose metabolism.