T lymphocyte SHP2-deficiency triggers anti-tumor immunity to inhibit colitis-associated cancer in mice.

Wen Liu,Qiang Xu,Yang Sun,Zhen Chen,Qiong Luo,Xiaolin Luo,Yanhong Gu,Yongqian Shu,Wenjie Guo,Gensheng Feng,Lihong Shen

doi:10.18632/oncotarget.13812

Abstract

Nonresolving inflammation is involved in the initiation and progression process of tumorigenesis. Src homology 2 domain-containing tyrosine phosphatase 2 (SHP2) is known to inhibit acute inflammation but its role in chronic inflammation-associated cancer remains unclear. The role of SHP2 in T cells in dextran sulfate sodium (DSS)-induced colitis and azoxymethane-DSS-induced colitis-associated carcinogenesis was examined using SHP2CD4−/− conditional knockout mice. SHP2 deficiency in T cells aggravated colitis with increased level of pro-inflammatory cytokines including IFN-γ and IL-17A. In contrast, the SHP2CD4−/− mice developed much fewer and smaller tumors than wild type mice with higher level of IFN-γ and enhanced cytotoxicity of CD8+ T cells in the tumor and peritumoral areas. At the molecular level, STAT1 was hyper-phosphorylated in T cells lacking SHP2, which may account for the increased Th1 differentiation and IFN-γ secretion. IFN-γ neutralization or IFN-γ receptor knockout but not IL-17A neutralization, abrogated the anti-tumor effect of SHP2 knockout with lowered levels of perforin 1, FasL and granzyme B. Finally, the expression of granzyme B was negatively correlated with the malignancy of colon cancer in human patients. In conclusion, these findings suggest a new strategy to treat colitis-associated cancer via targeting SHP2.

Highlights

The development of cancer is driven by various factors including genetic mutations [1] and epigenetic alterations [2]
To determine the functional role of Src homology 2 domain-containing tyrosine phosphatase 2 (SHP2) in CD4+ T cells during the development of acute colitis, we compared between T-cell-conditional SHP2-knockout mice with their age- and sex-matched wild type (WT) littermates (Supplementary Figure S1)
Compared with the WT littermates, dextran sulfate sodium (DSS) induced severe colitis in SHP2CD4−/− mice manifested by more body weight loss, higher disease activity index (DAI, a clinical parameter that reflects the severity of weight loss, rectal bleeding and stool consistency) and colon length shortening (Figure 1A, 1B)

Summary

Introduction

The development of cancer is driven by various factors including genetic mutations [1] and epigenetic alterations [2]. Solid tumors are typically infiltrated with immunogenic cells, including T lymphocytes, macrophages and myeloid-derived suppressive cells. CD4+ T cells are major players in orchestrating immune responses to tumor cells. Th1 cells can secrete IFN-γ, which activates cytotoxic T lymphocytes (CTLs), together mediating anti-tumor immunity. Th1 cells produce TNF-α and Th17 cells secrete IL-17, all of which may dampen immunity to tumor-associated antigens [5,6,7]. Depending on the subtypes of T cells and contexts of tumors, different molecular pathways and cellular processes may mediate distinct functional outcomes

Methods

Results

Conclusion