Breast Cancer Res Treat. 2015 Aug;153(1):21-30.

Poly (I: C) modulates the immunosuppressive activity of myeloid-derived suppressor cells in a murine model of breast cancer.

Forghani P; Edmund K Waller

Department of Hematology and Medical Oncology, Winship Cancer Institute, Emory University, Atlanta, GA, USA

 

Abstract

Polyinosinic-polycytidylic acid [Poly (I: C)], a ligand for Toll-like receptor (TLR-3), is used as an adjuvant to enhance anti-tumor immunity because of its prominent effects on CD8 T cells and NK cells. Myeloid-derived suppressor cells (MDSCs) are one of the main immunosuppressive factors in cancer, and their abnormal accumulation is correlated with the clinical stage of breast cancer and is an important mechanism of tumor immune evasion. Although Poly (I: C) is thought to have direct anti-tumor activity in different cell lines, its effect on immunosuppressive MDSCs in tumor-bearing animals has not been studied. 4T1-Luc, a metastatic breast cancer mouse cell line, was injected into the left flank of female BALB/c mice. Tumor-bearing mice were treated with i.p. injection of Poly (I: C) or PBS beginning on day 7 after tumor inoculation. WBCs and MDSCs were counted using coulter counter and stained for flow cytometry, respectively. Bioluminescent imaging was used to monitor tumor burden at multiple time points during the course of tumor growth. Poly (I: C) treatment led to a decrease in MDSC frequencies in BM, blood, and tumor compared to saline-treated control mice. Poly (I: C) treatment also abrogated the immunosuppressive function of MDSCs, concomitant with an increase in local T cell response of the immune system in a murine model of breast cancer. Poly (I: C) treatment decreases MDSC frequency and immunosuppressive function in 4T1-tumor-bearing hosts and effectively augments the activity of breast cancer immunotherapy.

PMID: 26208484

 

Supplement:

Targeting of MDSCs Using Pro-inflammatory Agent Poly (I: C) in Murine Model of Breast Cancer

Abstract:

Targeting of MDSCs is a promising therapeutic approach for cancer immunotherapy [1, 2]. An agonist of TLR-3, Poly (I: C), is currently being tested in human clinical trials as an adjuvant to anti-cancer vaccines and in combination with other therapies [3]. Although some data have been shown that Poly (I: C) induces a strong anti-tumor response and limited tumor growth in different mouse models [4], direct apoptosis of tumor cells has been considered to be the main mechanism which Poly (I: C) induces tumor regression. Since MDSCs are an essential part of immunosuppressive network induced by tumors [5-7], we hypothesized that Poly (I: C) might stimulate anti tumor adaptive immunity indirectly by inhibiting the immunosuppressive activity of MDSCs in murine model of breast cancer. We have explored this important question by investigating the function of Poly (I: C) on blood, tumor and BM-derived MDSCs in BALB/c mice bearing luciferase- transfected 4T1 breast cancer cells. Here, we highlight our recent findings and ongoing work to develop these findings into a novel therapeutic approach.

 

We are currently investigated the new mechanism by which poly (I; C) activate immune system [8]. To investigate the role of Poly (I: C) treatment in controlling tumor growth, we used BALB/c mice bearing luciferase- transfected 4T1 breast cancer cells. Figure 1 showing the blood content of MDSCs during tumor growth and after Poly (I: C) treatment. We found that PBS-treated mice had higher number of CD11b+Gr-1+ cells in the blood compared with Poly (I: C)- treated mice.

PF FIG1

 

 

Additionally bioluminescence imaging (Figure 2) represents a lower tumor burden in the Poly (I: C) treated group parallel with the decreased frequency of MDSCs and CD11b+Gr-1+ in the tumor microenvironment.

PF FIG2

 

Also we found a corresponding increase in the frequency of CD3+ TILs in the tumor microenvironment that revealed suppression of tumor growth correlates with MDSCs/ TIL ratio in tumor microenvironment following Poly (I: C) administration [8]. Decreased numbers of MDSCs in tumor was accompanied by skewing of cellular anti tumor immune response towards Th1 in Poly (I: C) treated mice compared with PBS-treated mice[8].Then to test whether the effect of Poly (I: C) on MDSC numbers was through direct regulation of MDSCs production in the bone marrow, we administrated Poly (I: C) once in a week for four weeks to both, tumor and non-tumor bearing naïve BALB/c mice and compared MDSC/IMCs numbers in the bone marrow. Reduction in frequency of CD11b+ GR-1+ IMCs (immature myeloid cell) s bone marrow of non-tumor bearing naïve BALB/c mice upon administration of Poly (I: C)(Figure.3).

PF FIG3

 

 

Our data demonstrate that treatment with poly I: C resulted in reduction in MDSCs infiltration into the tumor microenvironment of 4T1 breast tumor bearing mice through the inhibition of the generation of immature myeloid cells in the BM. Considering expression of TLR3 0n MDSCs [8], our study has established a direct evidence for Poly (I: C) effect on MDSCs through TLR3 and provides proof-of-concept for modulation of MDSCs and modification of immune response in breast cancer.

 

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