TY - JOUR
T1 - Standardized uptake value for 18F-fluorodeoxyglucose is a marker of inflammatory state and immune infiltrate in cervical cancer
AU - Floberg, John M.
AU - Zhang, Jin
AU - Muhammad, Naoshad
AU - DeWees, Todd A.
AU - Inkman, Matthew
AU - Chen, Kevin
AU - Lin, Alexander J.
AU - Rashmi, Ramachandran
AU - Jayachandran, Kay
AU - Edelson, Brian T.
AU - Siegel, Barry A.
AU - Dehdashti, Farrokh
AU - Grigsby, Perry W.
AU - Markovina, Stephanie
AU - Schwarz, Julie K.
N1 - Funding Information:
J.M. Floberg reports grants from the Radiological Society of North America during the conduct of the study. B.A. Siegel reports grants from the NIH, ASTRO Resident Research Seed Grant, and RSNA Resident Research Grant during the conduct of the study; grants and personal fees from the American College of Radiology, Imaginab, Inc., and Blue Earth Diagnostics; and personal fees from the American Medical Foundation for Peer Review and Education, Avid Radiopharmaceuticals, Inc., Capella Imaging, LLC, Curium Pharma, Radiological Society of North America, and Siemens Healthineers outside the submitted work. S. Markovina reports grants from the NCI during the conduct of the study and grants and nonfinancial support from GlaskoSmithKline outside the submitted work. J.K. Schwarz reports grants from NIH, ASTRO, and RSNA during the conduct of the study; grants from Goldman Sachs Philanthropy Cancer Research Fund, Siteman Investment Program, 2019 AACR– Bristol Myers Squibb Mid-career Female Investigator Grant, NIH; and nonfinancial support from Calithera Biosciences outside the submitted work. No disclosures were reported by the other authors.
Funding Information:
We would like to thank Marina Platik and the Anatomic and Molecular Pathology Core Laboratory at Washington University in St. Louis for their assistance in staining the TMA. We would also like to acknowledge Songyang Wang, MD, PhD, and Min Tan from Stephanie Markovina’s laboratory for their assistance with IHC and for supplying supplies, reagents, and expertise for investigating the JAK/STAT3 pathway. This work was supported in part by NIH R01CA181745 and the AACR–Bristol Myers Squibb Mid-career Female Investigator Award to J.K. Schwarz; by NIH K08CA237822 to S. Markovina, by NCI K22CA237839 to J. Zhang, and by ASTRO Resident Research Seed Grant 531448 and the RSNA Resident Research Grant to J.M. Floberg.
Publisher Copyright:
© 2021 American Association for Cancer Research.
PY - 2021/8/1
Y1 - 2021/8/1
N2 - Purpose: Chemoradiotherapy 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 with 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. IHC using a tissue microarray (TMA, N ¼ 82) was used to validate the CIBERSORT findings. The impact of macrophages on cervical cancer glucose metabolism was investigated in coculture experiments. Results: SUVmax <11.4 was most prognostic for FFP (P ¼ 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. Coculture of cervical cancer cells with macrophages or macrophage-conditioned media altered glucose uptake, and IL6 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.
AB - Purpose: Chemoradiotherapy 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 with 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. IHC using a tissue microarray (TMA, N ¼ 82) was used to validate the CIBERSORT findings. The impact of macrophages on cervical cancer glucose metabolism was investigated in coculture experiments. Results: SUVmax <11.4 was most prognostic for FFP (P ¼ 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. Coculture of cervical cancer cells with macrophages or macrophage-conditioned media altered glucose uptake, and IL6 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.
UR - http://www.scopus.com/inward/record.url?scp=85111649328&partnerID=8YFLogxK
U2 - 10.1158/1078-0432.CCR-20-4450
DO - 10.1158/1078-0432.CCR-20-4450
M3 - Article
C2 - 33820781
AN - SCOPUS:85111649328
SN - 1078-0432
VL - 27
SP - 4245
EP - 4255
JO - Clinical Cancer Research
JF - Clinical Cancer Research
IS - 15
ER -