Role of M1-polarized tumor-associated macrophages in the prognosis of advanced ovarian cancer patients

Antonio Macciò,Giulia Gramignano,Maria Cristina Cherchi,Luca Melis,Clelia Madeddu,Luciana Tanca

doi:10.1038/s41598-020-63276-1

Antonio Macciò, Giulia Gramignano + Show 4 more

Open Access

https://doi.org/10.1038/s41598-020-63276-1

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Abstract

The identification of prognostic and predictive markers is crucial for choosing the most appropriate management method for ovarian cancer patients. We aimed to assess the prognostic role of tumor-associated macrophage (TAM) polarization in advanced ovarian cancer patients. We carried out a prospective observational study that included 140 consecutive patients with advanced-stage high-grade serous ovarian cancer as well as patients with other histotypes of ovarian cancer and patients with ovarian metastasis from other sites between June 2013 and December 2018. Patients were enrolled at the time of laparoscopic surgery before receiving any antineoplastic treatment. We found that patients with high-grade serous papillary ovarian cancers had a prevalence of M1 TAMs, a higher M1/M2 ratio, and a longer overall survival (OS) and progression-free survival (PFS) than other patients. Regression analysis confirmed that there was a significant positive association between the M1/M2 ratio and an improved OS, PFS and platinum-free interval (PFI), both in the entire population and in patients stratified according to tumor type and initial surgery. Kaplan-Meier analysis was performed after the patients were divided into 2 groups according to the median M1/M2 ratio and revealed that patients with a high M1/M2 ratio had a higher OS, PFS and PFI than those with a low M1/M2 ratio. In conclusion, the prognostic and predictive role of TAM polarization in the tumor microenvironment could be of great clinical relevance and may allow the early identification of patients who are likely to respond to therapy. Further studies in a larger prospective sample are warranted.

Highlights

When defining the role of macrophage polarization in the epithelial serous ovarian cancer microenvironment, we found a prevalence of M1 cells with a high M1/M2 ratio among tumor-associated macrophages (TAMs)[2]
In this cohort of patients, we found that TAMs isolated from the ascites of primary high-grade serous ovarian cancer patients presented a prevalence of M1 macrophages (CD14+/CD80+/Glut1+ cells) with a higher M1/ M2 ratio than patients with different histotypes or ovarian metastasis from other sites (2.6 ± 0.8 vs 0.99 ± 0.4, 95% CI: 0.74–1.72; p = 0.006)
Since M1 polarization is closely related to increased glycolytic activity, glucose uptake analysis showed a higher mean fluorescence intensity in TAMs isolated from primary high-grade serous ovarian cancer patients than in those isolated from patients with different ovarian cancer histotypes or ovarian metastasis from other sites

Summary

Introduction

When defining the role of macrophage polarization in the epithelial serous ovarian cancer microenvironment, we found a prevalence of M1 cells with a high M1/M2 ratio among tumor-associated macrophages (TAMs)[2]. This M1 polarization was associated with cancer-related anemia and was correlated with the severity of anemia, IL-6 levels, and iron metabolism changes, which, as we have already demonstrated, are typical of advanced stage ovarian cancer patients[3]. In light of Thorsson’s findings, we assessed the correlation of the M1 TAM percentage and M1/M2 ratio in the tumor microenvironment with patient prognosis. We used our previous cohort of high-grade serous ovarian cancer patients[2] while increasing the sample size, and extending our evaluation to a cohort of patients with primary ovarian cancer with other histotypes (that are typically associated with worse prognosis and chemoresistance to platinum and its derivatives) and patients with ovarian metastasis from other sites

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