Reprograming of Tumor-Associated Macrophages in Breast Tumor-Bearing Mice under Chemotherapy by Targeting Heme Oxygenase-1

Abstract

Tumor-associated macrophages (TAMs) represent one of the most abundant components of the tumor microenvironment and play important roles in tumor development and progression. TAMs display plasticity and functional heterogeneity as reflected by distinct phenotypic subsets. TAMs with an M1 phenotype have proinflammatory and anti-tumoral properties whereas M2-like TAMs exert anti-inflammatory and pro-tumoral functions. Tumor cell debris generated during chemotherapy can stimulate primary tumor growth and recurrence. According to our previous study, phagocytic engulfment of breast tumor cell debris by TAMs attenuated chemotherapeutic efficacy through the upregulation of heme oxygenase-1 (HO-1). To verify the impact of HO-1 upregulation on the profile of macrophage polarization during cytotoxic therapy, we utilized a syngeneic murine breast cancer (4T1) model in which tumor bearing mice were treated with paclitaxel (PTX). PTX treatment markedly downregulated the surface expression of the M1 marker CD86 in infiltrated TAMs. Notably, there were significantly more cytotoxic CD8+ T cells in tumors of mice treated with PTX plus the HO-1 inhibitor, zinc protophorphyrin IX (ZnPP) than in mice treated with PTX alone. Interestingly, the tumor-inhibiting efficacy of PTX and ZnPP co-treatment was abrogated when macrophages were depleted by clodronate liposomes. Macrophage depletion also decreased the intratumoral CD8+ T cell population and downregulated the expression of Cxcl9 and Cxcl10. The expression of the M1 phenotype marker, CD86 was higher in mice injected with PTX plus ZnPP than that in mice treated with PTX alone. Conversely, the PTX-induced upregulation of the M2 marker gene, Il10 in CD11b+ myeloid cells from 4T1 tumor-bearing mice treated was dramatically reduced by the administration of the HO-1 inhibitor. Genetic ablation of HO-1 abolished the inhibitory effect of 4T1 tumor cell debris on expression of M1 marker genes, Tnf and Il12b, in LPS-stimulated BMDMs. HO-1-deficient BMDMs exposed to tumor cell debris also exhibited a diminished expression of the M2 macrophage marker, CD206. These findings, taken all together, provide strong evidence that HO-1 plays a pivotal role in the transition of tumor-inhibiting M1-like TAMs to tumor-promoting M2-like ones during chemotherapy.

Sanguinarine Regulates Tumor-Associated Macrophages to Prevent Lung Cancer Angiogenesis Through the WNT/β-Catenin Pathway

“…The results showed that macrophage clearance alone and Sanguinarine treatment alone could inhibit tumor growth, (Figure 4B), manifesting in the smallest tumor (Figure 4C) and the lightest tumor (Figure 4D). The percentage of CD11b+F4/80+ macrophages significantly decreased in the spleen and tumor tissue treated with macrophage clearance (Figure S3 and Figures 4F, S6B, E), which is consistent with previous reports (38)(39)(40). In addition, the group treated with CLPs effectively decreased tumor size and load (Figures 4B-D), indicating that macrophages contribute to neoplastic progression.…”

A Dynamic Transcriptome Map of Different Tissue Microenvironment Cells Identified During Gastric Cancer Development Using Single-Cell RNA Sequencing

“…Macrophages are a heterogeneous cell group with distinctive phenotypes and functions in complex microenvironments ( 26 ). Traditionally, these cells are divided into M1 (classically activated macrophage) and M2 types (alternatively activated macrophages) ( 27 ).…”

Debris-stimulated tumor growth: a Pandora’s box?

“…In the subthreshold inoculum model, instead of suppressing tumor growth, chemotherapy promoted tumor growth in small or dormant tumors via tumor-promoting debris [1,3]. Similarly, chemotherapygenerated tumor cell "debris" (apoptotic and necrotic cells and cell fragments) promotes cancer progression and metastasis via stimulating an eicosanoid-driven cytokine storm of pro-inflammatory and pro-angiogenic mediators [1,2,14,38,39,57,76], polarizing tumor-associated macrophages (TAMs) as well as inducing immunosuppression and limiting anti-tumor immunity [24,77,78]. Thus, new approaches to stimulate the clearance of tumor cell debris are urgently needed [1,21,40,[78][79][80].…”