Blockade of TNF-α signaling benefits cancer therapy by suppressing effector regulatory T cell expansion

Abstract

Effector but not naive regulatory T cells (Treg cells) can accumulate in the peripheral blood as well as the tumor microenvironment, expand during tumor progression and be one of the main suppressors for antitumor immunity. However, the underlying mechanisms for effector Treg cell expansion in tumor are still unknown. We demonstrate that effector Treg cell-mediated suppression of antitumor CD8C T cells is tumor-nonspecific. Furthermore, TNFR2 expression is increased in these Treg cells by Affymetrix chip analysis which was confirmed by monoclonal antibody staining in both hepatocellular carcinoma (HCC) and colorectal cancer (CRC) patients and murine models. Correspondingly, increased levels of TNF-a in both tissue and serum were also demonstrated. Interestingly, TNF-a could not only expand effector Treg cells through TNFR2 signaling, but also enhanced their suppressive activity against antitumor immunity of CD8 C T cells. Furthermore, targeting TNFR2 signaling with a TNF-a inhibitor could selectively reduce rapid resurgence of effector Treg cells after cyclophosphamide-induced lymphodepletion and markedly inhibit the growth of established tumors. Herein, we propose a novel mechanism in which TNF-a could promote tumor-associated effector Treg cell expansion and suggest a new cancer immunotherapy strategy using TNF-a inhibitors to reduce effector Treg cells expansion after cyclophosphamide-induced lymphodepletion.

Endoplasmic Reticulum Stress Causes Liver Cancer Cells to Release Exosomal miR‐23a‐3p and Up‐regulate Programmed Death Ligand 1 Expression in Macrophages

“…We found that GRP78 high HCC tissues recruited more CD68 + macrophages in the stroma, and in vitro studies demonstrated that Exo‐TMs polarized macrophages to the M2 phenotype. Moreover, there are evidences suggesting that cancer cells promote macrophage production of inflammatory mediators, such as IL‐6 and TNF‐α, to facilitate tumor metastasis . Here, we found that Exo‐TMs not only increased macrophage IL‐6 and TNF‐α expression but also up‐regulated protumor factor IL‐10 expression, suggesting that ER‐stressed HCC cells may “educate” macrophages toward TAMs to facilitate disease progression.…”

Novel insights into transcriptional dysregulation in colorectal cancer

“…Tumor Necrosis Factor Alpha (TNF-α) activates the transcription factor NFκB, thus promoting proliferation and metastasis of tumor cells [44,46]. Several studies have demonstrated the link between increased TNF mRNA levels in the tumor tissue and advanced stages of CRC [47][48][49], suggesting that targeting TNF-α can be applied in treatment of CRC, especially when it has progressed from ulcerative colitis [50,51]. However, some authors report suppression of this cytokine in tumor, attributed to promoter-methylation of the gene [52].…”

Potential targeting of B7‐H4 for the treatment of cancer

“…Treg cells can accumulate in both the peripheral blood and the cancer microenvironment and have been shown to expand during cancer progression suggesting that Treg cells may play a pivotal role in suppressing anti-tumor immunity. 100 In support of this hypothesis, Treg cell depletion or functional suppression results in augmented T-cell immune responses against cancer in both mice and humans. 101 As an additional link between B7-H4 and Treg cells, a study using human cervical carcinoma found that B7-H4 promoted the growth of Treg cells.…”