Ethanol Ablation Therapy Drives Immune-Mediated Antitumor Effects in Murine Breast Cancer Models

Corrine A Nief; Adam M Swartz; Erika Chelales; Lauren Y Sheu; Brian T Crouch; Nirmala Ramanujam; Smita K Nair

doi:10.3390/cancers14194669

Ethanol Ablation Therapy Drives Immune-Mediated Antitumor Effects in Murine Breast Cancer Models

Cancers (Basel). 2022 Sep 25;14(19):4669. doi: 10.3390/cancers14194669.

Authors

Corrine A Nief^{1

2}, Adam M Swartz³, Erika Chelales¹, Lauren Y Sheu³, Brian T Crouch¹, Nirmala Ramanujam^{1

4

5}, Smita K Nair^{3

6

7}

Affiliations

¹ Department of Biomedical Engineering, Duke University, Durham, NC 27708, USA.
² Stanford School of Medicine, Stanford University, Stanford, CA 94305, USA.
³ Department of Surgery, Duke University School of Medicine, Durham, NC 27708, USA.
⁴ Department of Pharmacology and Cancer Biology, Duke University, Durham, NC 27708, USA.
⁵ Duke Global Health Institute, Duke University, Durham, NC 27708, USA.
⁶ Department of Pathology, Duke University School of Medicine, Durham, NC 27708, USA.
⁷ Department of Neurosurgery, Duke University School of Medicine, Durham, NC 27708, USA.

Abstract

Ethanol ablation is a minimally invasive, cost-effective method of destroying tumor tissue through an intratumoral injection of high concentrations of cytotoxic alcohol. Ethyl-cellulose ethanol (ECE) ablation, a modified version of ethanol ablation, contains the phase-changing polysaccharide ethyl-cellulose to reduce ethanol leakage away from the tumor. Ablation produces tissue necrosis and initiates a wound healing process; however, the characteristic of the immunologic events after ECE ablation of tumors has yet to be explored. Models of triple-negative breast cancer (TNBC), which are classically immunosuppressive and difficult to treat clinically, were used to characterize the immunophenotypic changes after ECE ablation. In poorly invasive TNBC rodent models, the injury to the tumor induced by ECE increased tumor infiltrating lymphocytes (TILs) and reduced tumor growth. In a metastatic TNBC model (4T1), TILs did not increase after ECE ablation, though lung metastases were reduced. 4T1 tumors secrete high levels of granulocytic colony stimulating factor (G-CSF), which induces a suppressive milieu of granulocytic myeloid-derived suppressor cells (gMDSCs) aiding in the formation of metastases and suppression of antitumor immunity. We found that a single intratumoral injection of ECE normalized tumor-induced myeloid changes: reducing serum G-CSF and gMDSC populations. ECE also dampened the suppressive strength of gMDSC on CD4 and CD8 cell proliferation, which are crucial for anti-tumor immunity. To demonstrate the utility of these findings, ECE ablation was administered before checkpoint inhibitor (CPI) therapy in the 4T1 model and was found to significantly increase survival compared to a control of saline and CPI. Sixty days after tumor implant no primary tumors or metastatic lung lesions were found in 6/10 mice treated with CPI plus ECE, compared to 1/10 with ECE alone and 0/10 with CPI and saline.

Keywords: breast cancer; immunomodulation; low-resource settings; myeloid derived supressor cells; tumor ablation; tumor microenvironment.

Abstract

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