Immunosuppressive activity of cancer-associated fibroblasts in head and neck squamous cell carcinoma

Abstract

Cancer-associated fibroblasts (CAFs) have been shown to play an important role in angiogenesis, invasion, and metastasis. In the present study, we determined whether CAFs within the tumor microenvironment (TME) in head and neck squamous cell carcinoma (HNSCC) contributed to promoting immunosuppression and evasion from immune surveillance. Six pairs of CAFs and normal fibroblasts (NFs) were established from the resected tumor tissues of patients with HNSCC. The effects of CAFs and NFs on the functions of T cells were comparatively analyzed. CAFs expressed the co-regulatory molecules, B7H1 and B7DC, whereas NFs did not. The expression levels of cytokine genes, including those for IL6, CXCL8, TNF, TGFB1, and VEGFA, were higher in CAFs. T cell proliferation was suppressed more by CAFs or their supernatants than by NFs. Moreover, PBMCs co-cultured with the supernatants of CAFs preferentially induced T cell apoptosis and regulatory T cells over those co-cultured with the supernatants of NFs. A microarray analysis revealed that the level of genes related to the leukocyte extravasation and paxillin signaling pathways was higher in CAFs than in NFs. These results demonstrated that CAFs collaborated with tumor cells in the TME to establish an immunosuppressive network that facilitated tumor evasion from immunological destruction.

Transient immunological and clinical effectiveness of treating mice bearing premalignant oral lesions with PD‐1 antibodies

“…More difficult to explain is the underlying cause for the more rapid decay in this immune activity in mice receiving PD‐1 antibody treatment compared to the mice receiving control treatment. It is important to note that, in the HNSCC environment, there are multiple mechanisms contributing to the immune dysfunction including inhibitory mediators such and PGE 2 produced directly by the tumor cells as well as tumor‐induced immune inhibitory cells such as Treg, MDSC and the less mature CD34 + progenitor cells, infiltrating macrophages and endothelial cells 10, 11, 12, 13, 14. Studies have not, however, been conducted to determine at what point and in what sequence during progression of premalignant oral lesions to HNSCC these various inhibitory mediators and cells overcome the immune defenses.…”

“…These include tumor production of immune inhibitory mediators and tumor induction of host immune suppressor cells. Among the immune suppressive cells induced by HNSCC are Treg, inhibitory tumor‐associated macrophages and fibroblasts, myeloid‐derived suppressor cells (MDSC) and the less mature CD34 + progenitor cells 10, 11, 12, 13, 14. More recently, attention has focused on mechanisms involving activation of immune checkpoint signaling such as through PD‐1 ligand and its PD‐1 receptor.…”

The Roles of Mesenchymal Stromal/Stem Cells in Tumor Microenvironment Associated with Inflammation

“…These results indicated that TAFs collaborate with tumor cells and TME in order to establish immunosuppressive milieu and facilitate tumor evasion from immune system [77, 78]. …”

Cancer-associated fibroblasts promote an immunosuppressive microenvironment through the induction and accumulation of protumoral macrophages

“…In the TME, fibroblasts transdifferentiate into activated phenotype myofibroblasts through transforming growth factor beta (TGF-β) and interleukin (IL)-1 beta signaling [6, 7], and are known as cancer-associated fibroblasts (CAFs). We recently demonstrated that CAFs in squamous cell carcinoma of the head and neck directly and indirectly modulate effector T cell function during antitumor immune responses [8]. CAFs exhibit greater suppressor activity on T cell proliferation through co-regulatory molecules and immunosuppressive cytokines than normal fibroblasts.…”