Abstract 1175: A pro-tumorigenic mechanism of M2 tumor-associated macrophages in triple-negative breast cancer
Authors: Juncker-Jensen Anna , Stavrou Nicholas , Padmanabhan Raghav , Parnell Erinn , Kuo Judy , Leones Eric , Sahafi Flora , William Josette 
Published: August 2019

Introduction:

Triple-negative breast cancers (TNBCs) are defined as tumors that are negative for both estrogen, progesterone and HER-2 receptors. It is a heterogeneous subtype of breast cancer with a high propensity for systemic metastases and poor survival with only chemotherapy available for treatment. Compared to other hormone-positive breast cancer subtypes, TNBC features a unique tumor microenvironment (TME) characterized by a large number of tumor-infiltrating lymphocytes (TILs) and tumor-associated macrophages (TAMs) (1), and the increase of immune infiltrate with high levels of TILs predicts response to neoadjuvant chemotherapy as well as improved survival.

TAMs can be described as classically activated M1 types with pro-inflammatory antitumor functions, versus alternatively activated M2 types with immunosuppressive pro-tumor functions. It has been reported that the presence of M2 TAMs positively correlates with TNBC, hormone receptor negativity, as well as higher tumor proliferation (2-3). However, the mechanisms by which TAMs interact with TNBC cells and their phenotypes in TNBC versus estrogen receptor positive (ER+) patients is not well understood.

Experimental Procedures:

Using MultiOmyx, a proprietary, immunofluorescence (IF) multiplexing assay that enables visualization and characterization of up to 60 biomarkers on a single FFPE section (4), we have characterized TIL phenotypes, tumor proliferation and TAM activation in 15 FFPE tumors from TNBC and 5 tumors from ER+ patients.

Results:

Using a multiplex panel of 9 markers we found a 10-fold higher number of TILs and a 5-fold higher number of proliferating tumor cells in TNBC versus ER+ tumors. Furthermore, the proportion of T helper cells (CD3+CD4+) that were Tregs (CD3+CD4+FoxP3+) was increased from 26% to 43% in TNBC tumors. Interestingly, when analyzing TAMs we found that while ER+ tumors had a significantly higher proportion of M1 TAMs (CD68+HLA-DR+) than M2 TAMs (CD68+CD163+), this expression pattern was reversed in TNBC. When analyzing a possible correlation between the activation state of TAMs and the proliferation of tumor cells, we found a positive significant correlation between the presence of M2 TAMs and proliferating tumor cells (Pearson's correlation p&lt;0.05), only in TNBC and not in ER+ tumors. Conversely, the presence of M1 tumors showed a weak negative correlation to tumor cell proliferation, in both ER+ and TNBC tumors.

Conclusion:

These data are suggestive of a possible pathway in which an increase in alternatively activated immunosuppressive M2 TAMs in hormone receptor negative breast cancer tumors, are responsible for providing a suitable environment for tumor proliferation.

References:

1. Yu T & Di G, Chin J Cancer Res 2017;29(3):237.

2. Medrek C et al., BMC Cancer 2012;23(12):306.

3. Klingen TA et al., Hum Pathol 2017;(69):72.

4. Gerdes MJ et al. PNAS 2013;(110):11982.

Citation Format: Anna Juncker-Jensen, Nicholas Stavrou, Raghav Padmanabhan, Erinn Parnell, Judy Kuo, Eric Leones, Flora Sahafi, Josette William. A pro-tumorigenic mechanism of M2 tumor-associated macrophages in triple-negative breast cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 1175.