Polarisation of Tumor-Associated Macrophages toward M2 Phenotype Correlates with Poor Response to Chemoradiation and Reduced Survival in Patients with Locally Advanced Cervical Cancer

Abstract

Objectivewe 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).Methods84 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.ResultsAt 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.Conclusionspolarisation 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.

Inhibition of EphB4–Ephrin-B2 Signaling Reprograms the Tumor Immune Microenvironment in Head and Neck Cancers

“…Our TCGA analysis further shows that the M1/M2 ratio is a prognostic predictor of both disease-free survival and overall survival in the HNSCC patient population. Our data are in concordance with the published reports suggesting that polarization of TAMs toward a M2 phenotype, indicated by a lower M1/M2 ratio predicts for poor response to chemoradiation and shorter survival in locally advanced cervical cancer (60). The polarization of TAMs toward M1 phenotype upon inhibition of EphB4-ephrin-B2 is most evident when combined with RT.…”

Evaluating the Polarization of Tumor-Associated Macrophages Into M1 and M2 Phenotypes in Human Cancer Tissue: Technicalities and Challenges in Routine Clinical Practice

“…A higher M1/M2 ratio in cancer tissue usually signifies a favorable outcome. Petrillo et al (39) demonstrated that in locally advanced cervical cancers (LACC), a more frequent complete pathological response to chemotherapy (CT) or radiotherapy (RT) was observed in patients with high M1/M2 ratio. On the other hand, polarization of TAMs toward the M2 phenotype as reflected by lower M1/M2 ratio was an independent predictor for poor response to CT or RT and shorter survival in LACC (39).…”

Galectin-9 modulates immunity by promoting Th2/M2 differentiation and impacts survival in patients with metastatic melanoma

“…High numbers of macrophages in tumors are typically associated with a poor prognosis (38). Additionally, M2 polarized macrophages have been shown to be indicative of poor survival in lung and cervical cancer (39, 40). In the context of galectin-9, THP-1 monocytes modified to over express intracellular galectin-9 were shown to promote inflammatory cytokine production through NF-IL6 and AP-1 (41).…”