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Uterine cervical cancer displaying tumor-related leukocytosis: a distinct clinical entity with radioresistant feature
Seiji Mabuchi1, Yuri Matsumoto2, Mahiru Kawano2
1Affiliations of authors: Department of Obstetrics and Gynecology (SM, YM, MK, TS, RT, HK, TH, AK, KS, TK), Department of Molecular Pathology (KM, NM), Department of Radiation Oncology (YS), Department of Biomedical Statistics (TH), and Department of Pathology (EM), Osaka University Graduate School of Medicine, Osaka, Japan; Department of Obstetrics and Gynecology, Osaka Medical College, Osaka, Japan (MH); Department of Obstetrics and Gynecology, Yamagata University Graduate School of Medicine, Yamagata, Japan (HK). smabuchi@gyne.med.osaka-u.ac.jp.
Background:
Tumor-related leukocytosis (TRL) is occasionally found in patients with nonhematopoietic malignancies. We investigated the clinical implication of TRL and individualized treatment for TRL-positive cervical cancer, as well as the underlying biological mechanism.
Methods:
Clinical data from 258 cervical cancer patients treated with definitive radiotherapy were analyzed to investigate the association between TRL and treatment outcome. Clinical samples, cervical cancer cell lines, and a mouse model of cervical cancer were used to examine the mechanisms responsible for TRL in cervical cancer, focusing on the role of tumor-derived granulocyte colony-stimulating factor (G-CSF) and myeloid-derived suppressor cells (MDSCs). All statistical tests were two-sided.
Results:
TRL was statistically significantly associated with younger age (Wilcoxon rank sum test, P = .03), larger tumor size (Wilcoxon rank sum test, P = .006), advanced clinical stage (χ(2) test, P = .01), and shorter overall survival (Cox proportional hazard modeling and Wald tests, P < .001). Among cervical cancer patients, TRL was associated with upregulated tumor G-CSF expression (χ(2) test, P < .001), elevated serum G-CSF levels (Student t test, P = .03), larger spleens (Student t test, P = .045), and increased MDSC frequencies in the blood (Student t test, P < .001) compared with the TRL-negative patients. In vitro and in vivo experiments revealed that tumor-derived G-CSF was involved in the underlying causative mechanism of TRL and MDSCs induced by tumor-derived G-CSF are responsible for the rapidly progressive and radioresistant nature of TRL-positive cervical cancer. The administration of anti-Gr-1 neutralizing antibody or the depletion of MDSCs by splenectomy (n = 6 per group) inhibited tumor growth and enhanced radiosensitivity in TRL-positive cervical cancer xenografts (Wilcoxon rank sum test, P = .008 and P = .02, respectively).
Conclusions:
TRL is associated with resistance to radiotherapy among cervical cancer patients, and MDSC-targeting treatments may have therapeutic potential in these patients.
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