Postponing tumor onset and tumor progression can be achieved by alteration of local tumor immunity

Zhijie Liu,Jiangchao Li,Mingdian Wang,Chaonan Qian,Lisheng Zheng,Changzhi Li,Musheng Zeng,Mingming Yang,Lingling Guo,Yanxia Shi,Guanming Lu,Dehuan Xie,Lingbi Jiang,Yanhong Lang,Yan Mei,Lixia Peng,Bijun Huang

doi:10.1186/s12935-021-01765-7

Abstract

BackgroundIt has been known for years that the same genetic defects drive breast cancer formation, yet, the onset of breast cancer in different individuals among the same population differs greatly in their life spans with unknown mechanisms.MethodsWe used a MMTV-PyMT mouse model with different genetic backgrounds (FVB/NJ vs. C57BL/6J) to generate different cancer onset phenotypes, then profiled and analyzed the gene expression of three tumor stages in both Fvb.B6 and Fvb mice to explore the underlying mechanisms.ResultsWe found that in contrast with the FVB/N-Tg (MMTV-PyMT) 634Mul mice (Fvb mice), mammary tumor initiation was significantly delayed and tumor progression was significantly suppressed in the Fvb.B6 mice (generated by crossing FVB/NJ with C57BL/6J mice). Transcriptome sequencing and analysis revealed that the differentially expressed genes were enriched in immune-related pathways. Flow cytometry analysis showed a higher proportion of matured dendritic cells in the Fvb.B6 mice. The plasma levels of interleukin-6 (IL-6) and vascular endothelial growth factor (VEGF) were significantly reduced in the Fvb.B6 mice. IL-6 also impaired the maturation of bone marrow dendritic cells (BMDCs) of the Fvb mice in vitro.ConclusionAll these findings suggest that immunity levels (characterized by a reduced IL-6 level and intact DC maturation in Fvb.B6 mice) are the key factors affecting tumor onset in a murine mammary cancer model.

Highlights

It has been known for years that the same genetic defects drive breast cancer formation, yet, the onset of breast cancer in different individuals among the same population differs greatly in their life spans with unknown mechanisms
PyMT‐induced mammary tumor initiation is delayed in F1 hybrids with significant survival benefits for the hosts The Fvb mouse strain is susceptible to mammary tumors, while the B6 strain is more resistant [22]
After 2 days of coculturing with IL-6, we found that the surface expression of CD80 and CD86 on bone marrow dendritic cells (BMDCs) were significantly decreased upon IL-6 treatment (Fig. 6d–f ), suggesting that IL-6 suppressed the maturation of Dendritic cells (DCs) in Fvb mice

Summary

Introduction

It has been known for years that the same genetic defects drive breast cancer formation, yet, the onset of breast cancer in different individuals among the same population differs greatly in their life spans with unknown mechanisms. With 1.67 million new cases per year, it is the 5th ranked cause of death [2]. It is Mei et al Cancer Cell Int (2021) 21:97 mouse strain is susceptible to mammary tumors, while the C57BL/6J strain is more resistant to inflammationinduced mammary tumors [8]. One possible reason for this is that the major histocompatibility complex (MHC)related immunity pathway mediates resistance associated with the H-2b haplotype in the C57BL strain [9, 10]. Vascular endothelial growth factor (VEGF) is a critical factor that can inhibit the migratory ability and immune function of mature dendritic cells [14]. The VEGFR antagonist can impair dendritic cell maturation [15]

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