Breast cancer cell debris diminishes therapeutic efficacy through heme oxygenase-1-mediated inactivation of M1-like tumor-associated macrophages.

Abstract

Chemotherapy is commonly used as a major therapeutic option for breast cancer treatment, but its efficacy is often diminished by disruption of patient's anti-tumor immunity. Chemotherapy-generated tumor cell debris could hijack accumulated tumor-associated macrophages (TAMs), provoking tumor recurrence. Therefore, reprogramming TAMs to acquire an immunocompetent phenotype is a promising strategy to potentiate therapeutic efficacy. In this study, we analyzed the proportion of immune cells in the breast cancer patients who received chemotherapy. To validate our findings in vivo, we used a syngeneic murine breast cancer (4T1) model. Chemotherapy generates an immunosuppressive tumor microenvironment in breast cancer. Here, we show that phagocytic engulfment of tumor cell debris by TAMs reduces chemotherapeutic efficacy in a 4T1 breast cancer model. Specifically, the engulfment of tumor cell debris by macrophages reduced M1-like polarization through heme oxygenase-1 (HO-1) upregulation. Conversely, genetic or pharmacologic inhibition of HO-1 in TAMs restored the M1-like polarization. Our results demonstrate that tumor cell debris-induced HO-1 expression in macrophages regulates their polarization. Inhibition of HO-1 overexpression in TAMs may provoke a robust anti-tumor immune response, thereby potentiating the efficacy of chemotherapy.

• Authors: Seung Hyeon Kim, Soma Saeidi, Xiancai Zhong, Shin-Young Gwak, Ishrat Aklima Muna, Sin-Aye Park, Seong Hoon Kim, Hye-Kyung Na, Yeonsoo Joe, Hun Taeg Chung, Kyoung-Eun Kim, Wonshik Han, Young-Joon Surh
• Journal: Neoplasia (New York, N.Y.) (Neoplasia) Vol. 22 Issue 11 Pg. 606-616 (11 2020) ISSN: 1476-5586 [Electronic] United States
• PMID: 33039895 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2020 The Authors. Published by Elsevier Inc. All rights reserved.

Chemical References

• Biomarkers, Tumor
• Heme Oxygenase-1

Topics

• Animals
• Biomarkers, Tumor
• Breast Neoplasms (etiology, metabolism, pathology, therapy)
• Cell Line, Tumor
• Disease Models, Animal
• Disease Susceptibility
• Female
• Gene Expression Regulation, Neoplastic
• Heme Oxygenase-1 (genetics, metabolism)
• Humans
• Immunophenotyping
• Macrophage Activation (genetics, immunology)
• Mice
• Models, Biological
• Phagocytosis (genetics, immunology)
• Tumor Microenvironment (genetics, immunology)
• Tumor-Associated Macrophages (immunology, metabolism, pathology)