Cancer associated macrophage-like cells and prognosis of esophageal cancer after chemoradiation therapy

Abstract

Background: Cancer Associated Macrophage-Like cells (CAMLs) are polynucleated circulating stromal cells found in the bloodstream of numerous solid-tumor malignancies. Variations within CAML size have been associated with poorer progression free survival (PFS) and overall survival (OS) in a variety of cancers; however, no study has evaluated their clinical significance in esophageal cancer (EC).

Methods: To examine this significance, we ran a 2 year prospective pilot study consisting of newly diagnosed stage I-III EC patients (n = 32) receiving chemoradiotherapy (CRT). CAML sizes were sequentially monitored prior to CRT (BL), ~ 2 weeks into treatment (T1), and at the first available sample after the completion of CRT (T2).

Results: We found CAMLs in 88% (n = 28/32) of all patient samples throughout the trial, with a sensitivity of 76% (n = 22/29) in pre-treatment screening samples. Improved 2 year PFS and OS was found in patients with CAMLs < 50 μm by the completion of CRT over patients with CAMLs ≥ 50 μm; PFS (HR = 12.0, 95% CI = 2.7-54.1, p = 0.004) and OS (HR = 9.0, 95%CI = 1.9-43.5, p = 0.019).

Conclusions: Tracking CAML sizes throughout CRT as a minimally invasive biomarker may serve as a prognostic tool in mapping EC progression, and further studies are warranted to determine if presence of these cells prior to treatment suggest diagnostic value for at-risk populations.

Keywords: Biomarker; Cancer associated macrophage-like cell; Esophageal cancer; Prognostic.

Fig. 1

Example of a CAML, normal white blood cells (WBCs) and circulating tumor cells (CTCs) with size comparisons. Cells were stained with an antibody mixture of CD45 (purple), cytokeratin (green), and DAPI (light blue). a–d A CAML(white open triangle) which was -65 m in length and CD45 + & DAPI + . CAML was attached to a normal WBC − 10 m in length (white arrows) which appears CD45 + and DAPI + . e–h CTCs (white dashed arrows) are Cytokeratin + & CD45−.CTCs shown near to normal WBCs (white arrows) that are CD45 + and DAPI + .Normal WBCs are typically − 8–10 m cells highly expressive of CD45.CAMLs are large, typically CD45 + ,low Cytokeratin + , with polynucleated DAPI nucleus. CTCs are CD45-with high filamented Cytokeratin signal

Fig. 2

Kaplan–Meier Survival Estimates of CAML Size at BL, T1 and T2. a, c, and e Demonstrate patient PFS outcomes throughout treatment. b, d, and f Show patient OS outcomes throughout treatment

Fig. 3

Changes of CAML sizes in non-progressing or progressing patients before, during and after induction of CRT. Average trends in the largest CAML size were visualized by averaging all patients that did not progress within 24 months (a, b) or all patients that progressed within 24 months (c, d) black dotted lines. a, b 70% of patients that did not progress within 2 years had an increase in macrophage engorgement during CRT, with a decrease in engorgement after treatment completion. c, d 60% of patients that progressed within 2 years had a gradual increase in macrophage engorgement at every time point during CRT with an overall increase in after treatment completion. Patients with a single time, i.e.no sequential data available, are indicated by open circles