Serum amyloid A 1 induces suppressive neutrophils through the Toll‐like receptor 2–mediated signaling pathway to promote progression of breast cancer

Abstract

Immune inflammation plays a key role in breast cancer development, progression, and therapeutic efficacy. Neutrophils are crucial for the regulation of the suppressive tumor microenvironment and are associated with poor clinical survival. However, the mechanisms underlying the activation of suppressive neutrophils in breast cancer are poorly understood. Here, we report that breast cancer cells secrete abundant serum amyloid A 1 (SAA1), which is associated with the accumulation of suppressive neutrophils. High expression of SAA1 in breast cancer induces neutrophil immunosuppressive cytokine production through the activation of Toll-like receptor 2 (TLR2)mediated signaling pathways. These include the TLR2/myeloid differentiation primary response 88 (MYD88)-mediated PI3K/nuclear factor-κB signaling pathway and p38 MAPK-associated apoptosis resistance pathway, which eventually promote the progression of breast cancer. Our study shows a mechanistic link between breast cancer cell secretion of SAA1 and suppressive neutrophils that potentiate tumor progression.These findings provide potential therapeutic targets for breast cancer.

Diverse Neutrophil Functions in Cancer and Promising Neutrophil-Based Cancer Therapies

“…Neutrophils could create an immunosuppressive tumor microenvironment ( Figure 2 (B2)), primarily by the production of arginase [ 14 , 119 ], interleukin 10 (IL-10) [ 119 ], inducible nitric oxide synthase (iNOS) [ 119 ], and CCL17 [ 28 , 120 ]. In addition, TANs have been shown to express PD-L1 [ 82 , 121 , 122 , 123 ].…”

“…For example, Anselmi et al showed that human melanoma stem cells can activate and polarize neutrophil-like HL-60 cells toward the N2 phenotype via the production of polarizing factors such as TGF-β, IL-8, and IL-6 [ 142 ]. Niu et al showed that breast cancer cells modify neutrophils to an immunosuppressive phenotype by secreting serum amyloid A 1 (SAA1) [ 119 ]. SAA1 interacts with toll-like receptor 2 (TLR2) on neutrophils and promotes neutrophils to produce IL-10, arginase, and iNOS, indicating the immunosuppressive activities of SAA1-treated neutrophils.…”

“…In the 4T1 breast cancer model, neutrophil blocking with anti-LY6G mAb with or without anti-SAA1 mAb slowed tumor growth. The slowest tumor growth rate was observed when a combination of anti-LY6G and anti-SAA1 mAbs were used together [ 119 ].…”

“…( B1 ) Neutrophils produce ROS and RNS, which can cause genotoxicity and contribute to tumorigenesis [ 110 , 111 ]. ( B2 ) Neutrophils participate in creating an immunosuppressive tumor microenvironment by expressing PD-L1 on their surface, producing high levels of iNOS and ARG and secreting immunosuppressive mediators such as CCL17 and IL-10 [ 28 , 119 , 120 , 121 ]. ( B3 ) Neutrophils support tumor angiogenesis via the secretion of several factors: VEGF [ 24 ], MMP9 [ 24 ], IL-8 [ 126 ], and Bv8 [ 127 ].…”

“…Tumor cells and CAFs communicate with neutrophils through the production of EVs and several soluble factors. The main soluble factors are: TGF-β [ 14 ], SAA1 [ 119 ], CXCL1 [ 144 ], CXCL5 [ 163 ], IL-8 [ 165 ], Aβ [ 166 ], CTSC [ 174 ], and G-CSF [ 200 ]. The main effects of this communication are the polarization of neutrophils into the N2 phenotype and triggering NETosis.…”