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Background: A crucial role for the immune system has been proposed in the establishment and progression of head and neck squamous cell carcinoma (HNSCC). In this study, we investigated the cytokine and regulatory profiles of T cells in tumor draining lymph nodes (TDLNs) of patients with HNSCC. Results: The frequencies of CD4+TNF-α+ and CD4+TNF-αhi negatively were associated with poor prognostic factors such as LN involvement (P = 0.015 and P = 0.019, respectively), stage of the disease (P = 0.032 and P = 0.010, respectively) and tumor size (P = 0.026 and P = 0.032, respectively). Frequencies of CD8+IFN-γ+ and CD8+IFN-γ+ TNF-α+ T cells showed negative relationship with tumor grade (P = 0.035 and P = 0.043, respectively). While, the frequencies of CD4+IL-4+, CD8+IL-10+, CD8+IL-4+T cells were higher in advanced stages of the disease (P = 0.042, P = 0.041 and P = 0.030, respectively) and CD4+IFN-γ+TNF-α−, CD8+IL-4+ and CD8+IFN-γ+TNF-α− T cells were higher in patients with larger tumor size (P = 0.026 and P = 0.032, respectively). Negative associations were found between the frequencies of CD4+CD25+Foxp3+ and CD4+CD25+Foxp3+CD127low/− Treg cells and cancer stage (P = 0.015 and P = 0.059). Conclusion: This study shed more lights on the changes in immune profile of T cells in TDLNs of HNSCC. Larger tumor size and/or LN involvement were associated with lower frequencies of CD4+TNF-α+, CD8+IFN-γ+ and CD8+IFN-γ+TNF-α+ but higher frequency of CD4+IL-4+ T cells. Moreover, Foxp3+Tregs correlated with good prognostic indicators. [ABSTRACT FROM AUTHOR]

Certain chemo-drugs could induce immunogenic cell death (ICD) activating T cell antitumor immunity while trigger indoleamine-2,3-dioxygenase (IDO) upregulation suppressing immune responses. Moreover, to achieve therapeutic efficacies on both primary tumors and tumor draining lymph nodes (TDLNs) in the meantime is still a big challenge. In this study, transfersomes functionalized with a tumor targeting, cell penetrating peptide tLyp1 (CGNKRTR) was developed to co-encapsulate doxorubicin (DOX, ICD inducer) and 1MT (IDO inhibitor). The functionalized transfersomes were complexed with microneedles (MNs) to realize co-delivery towards primary tumors and TDLNs via transdermal administration. The transfersomes were concentrated in the needles of MNs and released with needle dissolution after insertion into skin. After being internalized by cells, DOX induced tumor ICD effect to promote DCs maturation and dramatically activated cytotoxic T lymphocytes (CD8+ T), while 1MT inhibited IDO activity in DCs and reduced the immunosuppressive Tregs, thus mitigating tumor suppressive microenvironment. The nano-complexed microneedles exhibited 2.2-fold suppression in tumor growth compared with the I.V. group, which significantly enhanced anti-tumor effect. [Display omitted] [ABSTRACT FROM AUTHOR]

• TNFR2 was expressed by B or T lymphocytes in breast tumor draining lymph nodes. • Lymphocytes of breast tumor draining LNs expressed negligible amounts of TNFR1. • TNFR1 expression was not induced by polyclonal activators in lymphocytes. • TNFR2 expression in B cells was associated with good prognosticators. Tumor necrosis factor-α (TNF-α) is a key cytokine in inflammation and a driving force for leukocyte migration and recruitment. However, it may exert contrasting effects on the immune responses depend on its differential binding to its receptors (TNFR1 or TNFR2). The expression of TNF receptors by lymphocytes in the tumor draining lymph nodes (TDLNs) has not been thoroughly investigated. Herein, the expression of TNFRs on lymphocytes in the breast TDLNs was assessed. 40 axillary LN samples were obtained from breast cancer patients. Mononuclear cells were isolated using Ficoll-Hypaque gradient centrifugation and stained with anti-CD3, CD4, CD8, CD19, TNFR1 and TNFR2 and subjected to flow cytometry. Results showed that TNFR2 was detected on unstimulated B or T cells in the breast TDLNs while TNFR1 was nearly absent on these cells. Short or long term activation did not increase the expression of TNFR1. The percentage of TNFR2+ cells was significantly higher in CD4+ compared to CD19+ or CD8+ cells. No significant association was observed between the percentage of TNFR2 expressing T cells and prognostic indicators. However, the percentage of TNFR2+ B cells in the metastatic LNs had negative associations with tumor grade and the number of involved LNs (P = 0.009 and P = 0.04, respectively). Collectively, TNFR2 was the main TNFR expressed by unstimulated B or T lymphocytes in the breast TDLNs and the frequency of TNFR2+ B cells was connected to good prognosticators. The effects of TNFR2 expression by lymphocytes of breast TDLNs on their functions requires more functional studies. [ABSTRACT FROM AUTHOR]

Abstract CD4+ CD25+ regulatory T (Treg) cells express the transcription factor FOXP3 and play an essential role in preventing autoimmunity. Abundant Treg cell accumulation in tumors and tumor draining lymph nodes (TDLNs) has been reported to correlate with both poor and favorable prognosis in various cancers, which suggests that Tregs may have multiple effects on antitumor immunity. However, the heterogeneity of tumor- and TDLN-infiltrating Treg cells remains unclear. Here we provide heterogeneity analysis of tumor infiltrating human CD4+ Treg cells and their matched adjacent tissues and TDLNs. We defined three different subpopulations of tumor- and TDLN-infiltrating Treg cells by Helios and CCR8 expression in pancreatic ductal adenocarcinoma (PDAC) and confirmed their functional heterogeneity. Helios+ CCR8+ Treg cells with potent suppressor function and limited IL-2 and IFN-γ secretion were identified in tumors and TDLNs. On the contrary, Helios− CCR8− Treg cells have impaired suppressive activity, and elevated expression of pro-inflammatory cytokines. More advanced grades of PDAC have predominantly Helios+ CCR8+ Treg cells and few Helios− CCR8− Treg cells both in tumors and TDLNs that suggests poor prognosis. These data could help further define the role of Treg cells and their functional role in tumors and TDLNs. [ABSTRACT FROM AUTHOR]

Abstract: FOXP3+ regulatory T cells (Tregs) play an important role in the maintenance of tumor immunity tolerance. Compared with conventional myeloid dentritic cells (mDCs), plasmacytoid dendritic cells (pDCs) exhibit poor immunostimulatory ability, and their interaction with T cells often promotes the development of Tregs. The aim of this study was to determine FOXP3+ Tregs and CD123+pDCs infiltration in colorectal cancer and tumor draining lymph node (TDLN), and to evaluate the clinical significance and relationship between pDCs infiltration and Tregs development in the CRC tolerogenic milieu. An immunohistochemical assay was conducted to assess FOXP3+Tregs and CD123+pDCs infiltration in tumor tissue and in metastatic-free TDLN (mfTDLN) and metastatic TDLN (mTDLN). The results showed that FOXP3+ Tregs infiltration was more frequent in tumor tissue than in adjacent normal mucosa (P <0.001). FOXP3+Tregs infiltration was associated with advanced TNM stage and lymph node metastasis (P <0.01 and P <0.01 for TNM stage and lymph node metastasis, respectively). Different from FOXP3+Tregs, CD123+pDCs frequencies were lower in most CRC tumor tissues, whereas the positive rate of CD123 expression in CRC was significantly higher than in adjacent normal mucosa tissue (P <0.01). Compared to mfTDLN, mTDLN was significantly enriched in FOXP3+ Tregs (P <0.01) and increased in pDC/mDC ratio (P <0.01). The statistical analysis demonstrated a significant correlation in both Tregs and pDC/mDC ratio in mTDLN. These results suggest that there are more FOXP3+ Tregs with a stronger prognostic significance which might promote tumor tolerance, and that CD123+pDCs might contribute to Tregs development in the CRC tolerogenic milieu. [Copyright &y& Elsevier]

Objective. In the present study we compared the lymphocyte composition of tumor draining lymph nodes (TDLN) in 13 cervical (CC) and 26 endometrial cancer (EC) patients with special emphasis on the suppressive CD4+ T cell subset constitutively expressing CD25 (T regulatory, Treg, cells).Methods. Microscopically uninvolved TDLNs (n = 122) collected at different distances from the primary tumor site were used. Proximal TDLN included obturator, and internal and external iliac nodes. Distal TDLN included common iliac, presacral, and aortic nodes. Sixteen relevant lymphocyte subsets were assessed. The proliferative response to PHA and TCR crosslinking, the suppressive activity of Treg cells, and IFN-γ and IL-4 production were also assessed.Results. Compared to EC patients, TDLN from CC patients contained a higher proportion of naive CD4+ and CD8+ cells (P < 0.01), a lower proportion of CD4+ pre-effector cells (P < 0.05), and a higher proportion of the most potent Treg cell subset identified by coexpression of a high level of CD25 and CD152 (P < 0.05). Functionally, Treg cells were anergic and efficiently inhibited other T cell proliferation, thereby fulfilling the requirements of genuine Treg cells. The proliferative response of TDLN to both PHA and TCR crosslinking tended to be lower in CC than EC patients and was inversely related to the Treg cell content in both type of tumors. No differences were noticed between CC and EC patients in terms of IFN-γ and IL-4 production. Using pairs of TDLN from individual patients, we showed that proximal TDLN in CC and EC patients displayed a higher CD4/CD8 ratio (P < 0.05 and 0.001, respectively) compared to distal TDLN of the same individual. By contrast, only in EC patients did proximal TDLN contained a proportion of Treg cells higher than distal TDLN (P < 0.02).Conclusions. The present data highlight differences in immune competency of TDLN in CC and EC patients, suggesting that the former is in a relative immunosuppressive status, and also underlines the importance of the proximity to the primary tumor site. [Copyright &y& Elsevier]