Diet-induced obesity accelerates oral carcinogenesis by recruitment and functional enhancement of myeloid-derived suppressor cells

Jianmin Peng,Juan Xia,Jiayu Zhang,Xiaoan Tao,Qinchao Hu,Xianyue Ren,Huan Li,Tong Wu,Chunyang Wang,Xijuan Chen,Ming Song,Yun Wang,Bin Cheng

doi:10.1038/s41419-021-04217-2

Abstract

Although obesity has been associated with an increased risk and aggressiveness of many types of carcinoma, whether it promotes squamous cell carcinoma remains unclear. To reveal the role of obesity in oral squamous cell carcinoma (OSCC) initiation and development, we used 4NQO-induced OSCC model mice to examine the impact of dietary obesity on carcinogenesis. The results showed that high-fat diet (HFD)-induced obesity significantly promoted the incidence of OSCC and altered the local immune microenvironment with the expansion of CD11b+Gr1+ myeloid-derived suppressor cells (MDSCs). The underlying mechanism that induced an immunosuppressive local microenvironment in obesity was the recruitment of MDSCs through the CCL9/CCR1 axis and enhancement of MDSC immunosuppressive function via intracellular fatty acid uptake. Furthermore, clinical samples verified the increase in infiltrated CD33+ (a marker of human MDSCs) cells in obese OSCC patients, and data from the TCGA dataset confirmed that CD33 expression was positively correlated with local adipocytes in OSCC. Survival analysis showed that enrichment of adipocytes and high expression of CD33 were associated with poor prognosis in OSCC patients. Strikingly, depletion of MDSCs significantly ameliorated HFD-promoted carcinogenesis in 4NQO-induced model mice. These findings indicate that obesity is also an important risk factor for OSCC, and cancer immunotherapy, especially targeting MDSCs, may exhibit greater antitumor efficacy in obese patients.

Highlights

Obesity is a serious worldwide health problem attracting public concern
The proliferation of T cells was RESULTS Diet-induced obesity accelerated oral carcinogenesis in a 4NQO-induced mouse model To elucidate whether diet-induced obesity promotes the development of oral squamous cell carcinoma (OSCC), C57BL/6 mice were exposed to either a NFD or a high-fat diet (HFD) for 8 weeks, and the NFD- and HFD-fed mice were subjected to the establishment of oral carcinogenesis induced by drinking 4NQO water
A retrospective study found that obese positive association between body mass index (BMI) and head and neck squamous cell patients with metastatic melanoma who received anti-PD-1/PDL-1 carcinoma (HNSCC) but only in nonsmokers [26], while central therapy had better progression-free survival (PFS) and overall survival (OS) than normal-weight patients [39]

Summary

Introduction

Obesity is a serious worldwide health problem attracting public concern. According to the World Health Organization (WHO), the incidence of obesity in adults has nearly tripled from 1975 to 2016, with over 650 million people affected [1, 2]. In addition to type 2 diabetes and other traditional comorbidities, the association between obesity and several cancers, such as breast, kidney (renal cell), colon, pancreas, gallbladder, and liver cancer, has been well established [3]. Whether obesity promotes the development of squamous cell carcinoma remains unclear. We found that obesity was associated with poor prognosis in early-stage (T1/ 2N0M0) oral squamous cell carcinoma (OSCC) patients [4]. Understanding how obesity impacts the initiation and development of OSCC may result in improved early intervention strategies to decrease oral cancer risk

Methods

Results

Conclusion