Expression of TNFR2 by regulatory T cells in peripheral blood is correlated with clinical pathology of lung cancer patients

Abstract

CD4(+)FoxP3(+) regulatory T cells (Tregs) represent a major cellular mediator of cancer immune evasion. The expression of tumor necrosis factor receptor type II (TNFR2) on Tregs is reported to identify the maximally suppressive Treg population in both mice and human. We therefore investigated the phenotype and function of TNFR2(+) Tregs present in the peripheral blood (PB) of 43 lung cancer patients. Further, the association of TNFR2 expression on Tregs with clinicopathological factors was analyzed. The results showed that in the PB of lung cancer patients, Tregs expressed markedly higher levels of TNFR2 than conventional T cells (Tconvs). Expression of TNFR2 appeared to correlate better than CD25(+) and CD127(-) with FoxP3 expression. PB TNFR2(+) Tregs in lung cancer patients were more proliferative and expressed higher levels of the immunosuppressive molecule CTLA-4, and consequently more potently suppressed IFNγ production by cocultured CD8 CTLs. More importantly, higher TNFR2 expression levels on Tregs were associated with lymphatic invasion, distant metastasis and more advanced clinical stage of lung cancer patients. Therefore, our study suggests that TNFR2(+) Tregs play a role in promoting tumor progressive metastasis and expression of TNFR2 by PB Tregs may prove to be a useful prognostic marker in lung cancer patients.

Treg activation defect in type 1 diabetes: correction with TNFR2 agonism

“…An under‐abundance of Tregs is associated with autoimmunity and an overabundance of Tregs found in cancer and infectious diseases 7 , 8 , 9 , 10 . A particular type of Treg, the aTreg—which expresses high levels of tumor necrosis factor receptor 2 (TNFR2)—is abundantly found in and around human and murine malignant tumors and in chronic infectious diseases such as tuberculosis where the host's immune response is hampered 7 , 8 , 9 , 10 , 11 . These disease states illustrate the use of TNFR2‐expressing Tregs as a very effective strategy to prevent a host immune response even when it is needed in cancer and infections.…”

“…One subgroup is resting Tregs (rTregs, CD4 + CD25 + Foxp3 + CD45RO − RA + ) and the other is activated Tregs (aTregs, CD4 + CD25 + Foxp3 + CD45RA ‐ RO + ) 5 . When rTregs are converted to aTregs, they display high expression of tumor necrosis factor (TNF) receptor 2. aTregs expressing high TFNR2 constitute the most immunologically suppressive Treg subgroup 6 , 7 , 8 , 9 , 10 , 11 …”

“…In functional assays, aTregs with high expression of TNFR2 are highly immunosuppressive, which makes them desirable for autoimmunity but not for cancer treatment. An overabundance of aTregs expressing TNFR2 drives cancer in mice and humans 11 , 12 , 13 , 14 …”

“…5 When rTregs are converted to aTregs, they display high expression of tumor necrosis factor (TNF) receptor 2. aTregs expressing high TFNR2 constitute the most immunologically suppressive Treg subgroup. [6][7][8][9][10][11] The TNFR2 receptor is a signaling protein that triggers Treg differentiation from resting to activated state and triggers Treg proliferation in normal mice and humans. 8,9 In vitro application of TNF or TNFR2 agonistic antibodies produces potent and homogeneous aTregs with high TNFR2 expression.…”

High immunosuppressive burden in cancer patients: a major hurdle for cancer immunotherapy

“…Negative role of Tregs through dampening favorable CD8 + T cell responses to tumor associated antigens has been reported in breast cancer patients and patients with low CD8 + T cells/Tregs ratio had a better survival benefit [11]. Tregs also play an important role in the progression and metastasis of lung cancer, the most lethal disease globally which has no effective therapies and expression of tumor necrosis receptor factor type II (TNRF2) by circulating Tregs in these patients correlated with poor clinical outcome [12,13]. The inhibitory effect of Tregs on CD4 + and CD8 + T cells can be abrogated by treatment with anti-chemokine receptor type-4 (CCR4) and anti-CD56 antibody in vitro which represent a novel strategy for the elimination of Tregs in the therapeutic settings of lung cancer patients [14].…”