Cancer-associated fibroblasts induce PDL1+ neutrophils through the IL6-STAT3 pathway that foster immune suppression in hepatocellular carcinoma

Abstract

Emerging evidence indicate that cancer-associated fibroblasts (CAFs) affect tumor progression by reshaping the tumor microenvironment. Neutrophils are prominent components of solid tumors and important in cancer progression. Whether the phenotype and function of neutrophils in hepatocellular carcinoma (HCC) are influenced by CAFs is not well understood. Herein, we investigated the effect of HCC-derived CAFs (HCC-CAFs) on the neutrophils and explored the biological role of this effect. We found that HCC-CAFs induced chemotaxis of neutrophils and protected them from spontaneous apoptosis. Neutrophils were activated by the conditioned medium from HCC-CAFs with increased expression of CD66b, PDL1, IL8, TNFa, and CCL2, and with decreased expression of CD62L. HCC-CAF-primed neutrophils impaired T-cell function through the PD1/PDL1 signaling pathway. We revealed that HCC-CAFs induced the activation of STAT3 pathways in neutrophils, which are essential for the survival and function of activated neutrophils. In addition, we demonstrated that HCC-CAF-derived IL6 was responsible for the STAT3 activation of neutrophils. Collectively, our results suggest that HCC-CAFs regulate the survival, activation, and function of neutrophils within HCC through an IL6–STAT3–PDL1 signaling cascade, which presents a novel mechanism for the role of CAFs in remodeling the cancer niche and provides a potential target for HCC therapy.

Cancer‐associated fibroblasts promote PD‐L1 expression in mice cancer cells via secreting CXCL5

“…Evidences have shown the vital role of CAFs in cancer evasion of the immune surveillance, including hepatocellular carcinoma (HCC), esophageal cancer, CRC and melanoma . It was reported that CAFs secreted cytokines, such as, IL‐6, IL‐4, IL‐8, IL‐10, tumor necrosis factor (TNF), TGF‐β, C‐C motif chemokine ligand 2 (CCL2), CCL5, C‐X‐C motif chemokine ligand CXCL9, CXCL10, CXCL12, have direct and/or indirect implications for tumor immunity .…”

“…It is acknowledged that cytokines serve as mediators in shaping tumor microenvironment and facilitating tumor progression . Previous studies have reported that C‐X‐C motif chemokine ligand 12 (CXCL12), interferon‐γ (IFN‐γ), CXCL9/10/11 and IL6 promoted PD‐L1 expression in cancer cells . In this regard, we postulated that CAFs‐derived cytokines might promote PD‐L1 expression.…”

“…9,10 Previous studies have reported that C-X-C motif chemokine ligand 12 (CXCL12), interferon-γ (IFN-γ), CXCL9/10/11 and IL6 promoted PD-L1 expression in cancer cells. [11][12][13][14] In this regard, we postulated that CAFs-derived cytokines might promote PD-L1 expression.…”

The systemic inflammatory response as a source of biomarkers and therapeutic targets in hepatocellular carcinoma

“…A recent study has also revealed the role of HCC derived CAFs in fostering neutrophil mediated immune suppression in HCC. Specifically, HCC‐CAF derived IL‐6 was able to induce PD‐L1+ neutrophils via the JAK‐STAT3 pathway, which in turn impaired T cell function through PD‐1/PD‐L1 signalling and hence facilitated HCC progression …”

The influence of microenvironment on tumor immunotherapy

“…Interestingly, tumor‐associated stromal cells/CAFs themselves also expressed PD‐L1 to suppress CD8 + antitumor immune responses in response to the inflammatory secretome from human colon cancer cells, and pre‐inflammatory cytokine TNFα and IL‐1β induced CXCL8/CCL5 secretion in the co‐culture of CAFs and triple negative breast cancers , suggesting that the inflammation also regulates the immunological response of CAFs/stromal cells in the TME. In addition, CAFs in HCC regulate the survival and activation of neutrophils through the IL‐6–signal transducer and activator of transcription (STAT) 3–PD‐L1 signaling pathway and consequently affect the function of T cells . Even after high‐dose irradiation, CAFs maintain their powerful immunosuppressive effect over activated T cells .…”