Anti-TGF-β attenuates tumor growth via polarization of tumor associated neutrophils towards an anti-tumor phenotype in colorectal cancer

Abstract

Tumor associated neutrophils (TANs) play important roles in the progress of CRC. Since tumor microenvironments could influence the phenotypes of TANs, altering the tumor microenvironment to polarize the phenotype of TANs may be a new strategy for tumor treatment. This study aims to investigate the effect of anti-TGF-β on the polarization of TANs from a pro-tumor phenotype towards an anti-tumor phenotype in CRC. In this work, CRC patients had more infiltration of TANs and higher expression of TGF-β in CRC tissue when compared with the controls. In vitro, SW480 cells were co-cultured with primed neutrophils, which simulated the TANs in the tumor microenvironment, and TGF-β was blocked by anti-TGF-β (1D11) in order to polarize TANs. Anti-TGF-β treatment increased the cytotoxicity of TANs and decreased the metastatic chemoattractants secreted by TANs, and ultimately increased the apoptosis of CRC cells significantly while remarkably suppressing the migration of tumor cells. The changes of signaling pathways in the TANs and tumor cells were explored. The results showed that anti-TGF-β attenuated CRC may be partly mediated by suppression of PI3K/AKT signaling pathways in TANs and partly mediated by suppression of TGF-β/Smad signaling pathways in tumor cells. Furthermore, the tumor in the mice treated with 1D11 was obviously smaller and had reverse tumorigenesis compared with the controls, while neutrophil depletion reduced the anti-tumor effect of 1D11. Our data suggest that anti-TGF-β attenuates tumor growth via the polarization of TANs to an anti-tumor phenotype in CRC, which provides new strategies for CRC treatment.

Toward Regulatory Effects of Curcumin on Transforming Growth Factor-Beta Across Different Diseases: A Review

“…Upstream oncogenic factors such as HOXD9 stimulate expression of TGF-β, leading to enhanced proliferation and growth of tumor cells ( Wardhani et al, 2020 ). Notably, TGF-β overexpression induces resistance of cancer cells into chemotherapy ( Qin et al, 2020 ). Consequently, studies have focused on inhibition of TGF-β signaling pathway in cancer therapy.…”

TGF-β in Cancer: Metabolic Driver of the Tolerogenic Crosstalk in the Tumor Microenvironment

“…Following this observation, the same group found that in tumors TGF-β sustains the generation of TANs with a protumoral phenotype (N2); on the other hand, the pharmacological blockade of TGF-β promotes the recruitment and activation of antitumoral (N1) TANs in two different tumor types (NSCLC and mesothelioma) finally leading to enhanced anti-tumor immunity in tumor-bearing mice [ 131 ]. Paralleling data were proposed in colon rectal cancer; the use of anti-TGF-β (1D11) in vitro promoted the functional skewing of neutrophils, that upon coculturing with tumor cells, increased their cytotoxicity and decreased the release of pro-metastatic factors [ 132 ]. Through the same mechanisms, the treatment with anti-TGF-β reduced tumor growth in vivo in an azoxymethane (AOM) and dextran sulfate sodium (DSS) induced colon rectal cancer mouse model [ 132 ].…”

“…Paralleling data were proposed in colon rectal cancer; the use of anti-TGF-β (1D11) in vitro promoted the functional skewing of neutrophils, that upon coculturing with tumor cells, increased their cytotoxicity and decreased the release of pro-metastatic factors [ 132 ]. Through the same mechanisms, the treatment with anti-TGF-β reduced tumor growth in vivo in an azoxymethane (AOM) and dextran sulfate sodium (DSS) induced colon rectal cancer mouse model [ 132 ]. More recently, a novel mechanism of T cell suppression caused by TGF-β-mediated neutrophil activation has been described in mouse model of colon adenomas [ 133 ].…”

The Neutrophil: The Underdog That Packs a Punch in the Fight against Cancer

“…This inhibitory effect of TGF-β on neutrophils argues for the use of TGF-β antagonists to improve neutrophil-mediated anticancer immune responses. Indeed, the blocking of TGF-β with neutralizing TGF-β monoclonal antibody (1D11) polarized TANs toward an N1 phenotype, yielding a significant increase in colorectal carcinoma cell death [ 64 ]. Furthermore, TGF-β blockade increased the level of neutrophil-attracting chemokines and increased the influx of N1 neutrophils into the tumor, with increased cytotoxic potential both in vitro and in vivo [ 20 ].…”