Polarisation of Tumor-Associated Macrophages toward M2 Phenotype Correlates with Poor Response to Chemoradiation and Reduced Survival in Patients with Locally Advanced Cervical Cancer.
OBJECTIVE
We investigate the prognostic role of pre-treatment ratio between Type 1 (M1) and Type 2 (M2) tumor-associated macrophages (TAMs) in locally advanced cervical cancer (LACC) patients treated with chemoradiation (CT/RT).


METHODS
84 consecutive LACC patients treated with cisplatin-based CT/RT for a total dose of 50.0 Gy, followed by radical surgery were analysed. Double-staining immunohistochemistry of CD163/p-STAT, CD68/pSTAT1, CD163/c-MAF, and CD68/c-MAF was performed on tumor samples taken at the time of diagnosis. TAMs with CD163+pSTAT1+, or CD68+pSTAT1+ were defined M1; CD163+c-MAF+ or CD68+c-MAF+ defined the M2 phenotype. The number of M1 and M2 cells was counted at low magnification by evaluating for each case the same tumour area. The ratio between M1 and M2 (M1/M2) was finally calculated.


RESULTS
At diagnosis, we observed a direct correlation between the number of circulating monocytes and of TAMs (p-value = 0.001). Patients with high M1/M2 experienced more frequently complete pathologic response (no residual tumor) to CT/RT, compared to cases with low M1/M2 (55.0% Vs 29.5%; p-value = 0.029). At multivariate analysis M1/M2 (OR = 2.067; p-value = 0.037) emerged as independent predictor of pathologic response to CT/RT. Women with high M1/M2 showed a longer 5-yrs Disease-free (67.2% Vs. 44.3%; p-value = 0.019), and 5-yrs Overall (69.3% Vs. 46.9%; p-value = 0.037) survival, compared to cases with low M1/M2. The presence of a high M1/M2 ratio was independently associated with an unfavourable survival outcome in multivariate analysis.


CONCLUSIONS
Polarisation of TAMs toward a M2 phenotype, as reflected by a lower M1/M2 ratio, is an independent predictor of poor response to CT/RT, and shorter survival in LACC.
Department of Obstetrics and Gynecology, Gynecologic Oncology Unit, Catholic University of the Sacred Heart, Rome, Italy; Department of Oncology, Gynecologic Oncology Unit, Foundation "John Paul II" Catholic University of the Sacred Heart, Campobasso, Italy.
Marco
M
Petrillo
Department of Human Pathology, Division of Gynecologic Pathology, Catholic University of the Sacred Heart, Rome, Italy.
Gian Franco
GF
Zannoni
Department of Obstetrics and Gynecology, Gynecologic Oncology Unit, Catholic University of the Sacred Heart, Rome, Italy.
Enrica
E
Martinelli
Department of Obstetrics and Gynecology, Gynecologic Oncology Unit, Catholic University of the Sacred Heart, Rome, Italy.
Luigi
L
Pedone Anchora
Department of Obstetrics and Gynecology, Gynecologic Oncology Unit, Catholic University of the Sacred Heart, Rome, Italy.
Gabriella
G
Ferrandina
Department of Obstetrics and Gynecology, Gynecologic Oncology Unit, Catholic University of the Sacred Heart, Rome, Italy.
Giovanna
G
Tropeano
Division of Gynecologic Oncology, St. Maria Hospital, University of Perugia, Terni, Italy.
Anna
A
Fagotti
Department of Obstetrics and Gynecology, Gynecologic Oncology Unit, Catholic University of the Sacred Heart, Rome, Italy.
Giovanni
G
Scambia
D000328:Adult; D000368:Aged; D016764:Cell Polarity; D005260:Female; D006801:Humans; D007150:Immunohistochemistry; D016130:Immunophenotyping; D008264:Macrophages / Q000276:immunology*; D008875:Middle Aged; D016019:Survival Analysis; D002583:Uterine Cervical Neoplasms / Q000188:drug therapy / Q000276:immunology* / Q000532:radiotherapy; D055815:Young Adult