Toll-like Receptors in Regulatory T Cells of Patients With Head and Neck Cancer&lt;alt-title&gt;TLRs in T-reg Cells of HNSCC Patients&lt;/alt-title&gt;

Wild, Clarissa A.; Brandau, Sven; Lindemann, Monika; Lotfi, Ramin; Hoffmann, Thomas; Lang, Stephan; Bergmann, Christoph

doi:10.1001/archoto.2010.195

Cited by 27 publications

(19 citation statements)

References 25 publications

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“…This is in contrast to the majority of results reported by previous HNSCC studies where Tregs have been found to be increased in the cancer patients [10,22,30,31]. However, not all cancer publications report an elevated trend, with some observing no significant difference in the frequency of Tregs in the peripheral circulation of patients and healthy donors, including one study examining oral SCC [32,33].…”

Section: Discussioncontrasting

confidence: 73%

CD45RA-Foxp3high but not CD45RA+Foxp3low suppressive T regulatory cells increased in the peripheral circulation of patients with head and neck squamous cell carcinoma and correlated with tumor progression

Sun

et al. 2014

J Exp Clin Cancer Res

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BackgroundT regulatory cells (Tregs) contribute to the progression of head and neck squamous cell carcinoma (HNSCC) by suppressing antitumor immunity. However, little is known regarding the functional heterogeneity of Tregs in HNSCC patients.MethodsUsing multicolor flow cytometry, the frequency of three Treg subsets, separated on the basis of CD45RA and Foxp3, from the peripheral circulation of newly-presenting HNSCC patients (19 oral cavity squamous cell carcinoma, 20 hypopharyngeal squamous cell carcinoma, 18 nasopharyngeal squamous cell carcinoma, 19 oropharyngeal squamous cell carcinoma, and 36 laryngeal squamous cell carcinoma) were assessed with regard to 31 healthy donors and clinicopathological features. Moreover, the functional capacity of each Treg subsets was evaluated based on CD45RA and CD25 expression.ResultsThe frequency of Tregs in the peripheral circulation of HNSCC patients as a whole cohort was higher than in healthy donors (P < 0.0001). However, the frequency of Tregs was similar between patients with oral cavity squamous cell carcinoma and healthy donors (P = 0.269). Further dividing Tregs into three subsets based on Foxp3 and CD45RA expression revealed that the frequency of CD45RA-Foxp3high Tregs and CD45RA-Foxp3lowCD4+ T cells in patients with HNSCC developing from different subsites was higher than in healthy donors (P < 0.0001, P < 0.0001), whereas the frequency of CD45RA+Foxp3low Tregs was lower than in healthy donors (P < 0.0001). Functionally study revealed that CD45RA-CD25+++ Tregs significantly inhibit the proliferation of CD4+CD25- T cells (P < 0.001) and secrete lower levels of cytokines (P < 0.01) compared with CD45RA-CD25++CD4+ T cells. Importantly, the frequency of CD45RA-Foxp3high Tregs positively correlate with tumor stage (P < 0.0001) and nodal status (P < 0.0001).ConclusionsCD45RA-Foxp3high Tregs increase in the peripheral circulation of HNSCC patients, and correlate with tumor stage and nodal status; suggesting a role in tumor progression which may be manipulated by future immunotherapy.

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Section: Discussioncontrasting

confidence: 73%

CD45RA-Foxp3high but not CD45RA+Foxp3low suppressive T regulatory cells increased in the peripheral circulation of patients with head and neck squamous cell carcinoma and correlated with tumor progression

Sun

et al. 2014

J Exp Clin Cancer Res

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“…A short exposure of Treg to cisplatin prior to activation appears to protect them from AICD and is mediated by elevated expression levels of survival proteins, Bcl-2 and Bcl-xL, and lower levels of pro-apoptotic Bax than those observed in T conv (Figure 5). Still another possibility is that toll like receptors (TLR) present on Treg (32) and signaling in response to ligands released by radiation-induced tissue damage activate the PI3K/Akt survival pathway, protecting Treg from effects of CRT. Such TLR-mediated chemoresistance has been previously described for tumor cells (33–35).…”

Section: Discussionmentioning

confidence: 99%

Effects of Adjuvant Chemoradiotherapy on the Frequency and Function of Regulatory T Cells in Patients with Head and Neck Cancer

Schuler

Harasymczuk

Schilling

et al. 2013

Clinical Cancer Research

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Purpose Regulatory T cells (Treg) accumulate in tumor tissues and the peripheral blood of cancer patients and may persist after therapies. This cross-sectional study examines effects of adjuvant chemo-radiotherapy (CRT) on Treg numbers and function in head and neck squamous cell carcinoma (HNSCC) patients. Experimental design The frequency and absolute numbers of CD4+, ATP-hydrolyzing CD4+CD39+ and CD8+ T cells and expression levels of CD39, CD25, TGF-β-associated LAP and GARP on Treg were measured by flow cytometry in 40 healthy donors (NC) and 71 HNSCC patients (29 untreated with active disease (AD); 22 treated with surgery; 20 treated with CRT). All treated subjects had no evident disease (NED) at the time of phlebotomy. In an additional cohort of 40 subjects with AD (n=15), NED (n=10) and NC (n=15), in vitro sensitivity of CD4+ T cell subsets to cisplatin and activation-induced cell death (AICD) was tested in Annexin V-binding assays. Results CRT decreased the frequency of circulating CD4+ T cells (p<0.002) but increased that of CD4+CD39+ Treg (p≤0.001) compared to untreated or surgery-only patients. Treg frequency remained elevated for >3 years. CRT increased surface expression of LAP, GARP and CD39 on Treg. In vitro, Treg were resistant to AICD or cisplatin but conventional CD4+ T cells (Tconv) were not. CRT-induced Treg from AD or NC subjects up-regulated pro-survival proteins, while Tconv up-regulated pro-apoptotic Bax. Conclusions Highly suppressive, cisplatin-resistant Treg increase in frequency and persist after CRT and could be responsible for suppression of anti-tumor immune responses and recurrence in HNSCC.

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“…This suggests that autophagy defects may increase oxidized HMGB1. Tregs, especially in cancer patients, express both HMGB1-recognizing receptors TLR4 and RAGE [190]. HMGB1 increased secretion of IL-10 and the suppressive capacity in Tregs in a RAGE-dependent manner.…”

Section: Regulatory T Cellsmentioning

confidence: 99%

Until Death Do Us Part: Necrosis and Oxidation Promote the Tumor Microenvironment

Lotfi

Kaltenmeier

Lotze

et al. 2016

Transfus Med Hemother

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Tumor proliferation is concomitant with autophagy, limited apoptosis, and resultant necrosis. Necrosis is associated with the release of damage-associated molecular pattern molecules (DAMPs), which act as ‘danger signals', recruiting inflammatory cells, inducing immune responses, and promoting wound healing. Most of the current treatment strategies for cancer (chemotherapy, radiation therapy, hormonal therapy) promote DAMP release following therapy-induced tumor death by necroptosis and necrosis. Myeloid cells (monocytes, dendritic cells (DCs), and granulocytes), as well as mesenchymal stromal cells (MSCs) belong to the early immigrants in response to unscheduled cell death, initiating and modulating the subsequent inflammatory response. Responding to DAMPs, MSCs, and DCs promote an immunosuppressive milieu, while eosinophils induce oxidative conditions limiting the biologic activity of DAMPs over time and distance. Regulatory T cells are strongly affected by pattern recognition receptor signaling in the tumor microenvironment and limit immune reactivity coordinately with myeloid-derived suppressor cells. Means to ‘aerobically' oxidize DAMPs provide a novel strategy for limiting tumor progression. The present article summarizes our current understanding of the impact of necrosis on the tumor microenvironment and the influence of oxidative conditions found within this setting.

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Toll-like Receptors in Regulatory T Cells of Patients With Head and Neck Cancer<alt-title>TLRs in T-reg Cells of HNSCC Patients</alt-title>

Cited by 27 publications

References 25 publications

CD45RA-Foxp3high but not CD45RA+Foxp3low suppressive T regulatory cells increased in the peripheral circulation of patients with head and neck squamous cell carcinoma and correlated with tumor progression

CD45RA-Foxp3high but not CD45RA+Foxp3low suppressive T regulatory cells increased in the peripheral circulation of patients with head and neck squamous cell carcinoma and correlated with tumor progression

Effects of Adjuvant Chemoradiotherapy on the Frequency and Function of Regulatory T Cells in Patients with Head and Neck Cancer

Until Death Do Us Part: Necrosis and Oxidation Promote the Tumor Microenvironment

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