Treatment to sustain a Th17‐type phenotype to prevent skewing toward Treg and to limit premalignant lesion progression to cancer

Abstract

While immune suppression is a hallmark of head and neck squamous cell carcinoma (HSNCC), the immunological impact of premalignant oral lesions, which often precedes development of HNSCC, is unknown. The present study assessed the changes in splenic and draining lymph node CD4+cell populations and their production of select cytokines that occur in mice with carcinogen-induced premalignant oral lesions and the changes that occur as lesions progress to oral cancer. These studies found skewing toward Th1 and Th17-type phenotypes in the spleen and lymph nodes of mice with premalignant oral lesions and a shift to Treg as lesions progress to cancer. Since the role of Th17 cells in the progression from premalignant lesions to cancer is not clear, studies determined the immunological and clinical effect of treating mice bearing premalignant oral lesions with a TGF-β type 1 receptor inhibitor plus IL-23 as an approach to sustain the Th17 phenotype. These studies showed that the treatment approach not only sustained the Th17 phenotype, but also increased distal spleen cell and regional lymph node cell production of other stimulatory/inflammatory mediators and slowed premalignant lesion progression to cancer.

T-helper and T-regulatory cells modulation in head and neck squamous cell carcinoma

“…These data are sustained by studies in a murine model of 4-nitroquinoline-1-oxide induced oral carcinogenesis, where the progression from premalignant lesion to oral squamous cell carcinoma (OSCC) was characterized by a progressive increase of Th17 cells and IL-17. 4,31 How Th17 cells increase may be a favorable factor in tumor progression is still a matter of debate; nevertheless, one convincing hypothesis is that Th17 cells might have a significant role in promoting intra-tumor angiogenesis. 29 IL-17 steadily increases during HNSCC progression.…”

“…30 Indeed, although HNSCC patients have lower IL-17 plasma levels than patients harbouring premalignant lesions, their levels are higher than those in healthy controls. 31,32 Above reported data demonstrate that IL-17 increases during HNSCC progression, although a slight decrease is often observed in the latest phases, probably due to the high levels of TGFb, which may inhibit Th17 differentiation while promoting regulatory T (Treg) cells differentiation. 32 On the other hand, Punt and coworkers did not find any significant variation in T cells frequency between OSCC and healthy controls.…”

“…Thus, a shift in cytokine milieu form the Th17 sustaining pro-inflammatory IL-23 toward TGFb may easily result in a significant skew toward Treg as premalignant lesions progress to oral cancer. 31 …”

HNSCC subverts PBMCs to secrete soluble products that promote tumor cell proliferation

“…Th17 is the most anti-tumoral phenotype of T-cells [ 39 , 40 ]. Exposure of CD4+ T-cells to CM from HNSCC for 96h resulted in a significant decrease of gene expression of nuclear receptor ROR- t (ROR-gt), which was supported by the significant decrease of the percentage of Th17 cells (CD4+/IL17A+) (Figure 3A-3C ).…”

Immunomodulatory role of bitter melon extract in inhibition of head and neck squamous cell carcinoma growth

“…Th17 level has been shown to be increased in patients with ovarian cancer, cervical cancer, hypopharyngeal carcinoma, gastric cancer, and lung cancer, with a shift from Th17 to Treg cells in advanced disease [18]. In contrast, the premalignant epidermal squamous lesions in mouse model demonstrated increased induction of Th17 cells to coincide with tumor regression [19].…”