Neuropilin‐1 expression identifies a subset of regulatory T cells in human lymph nodes that is modulated by preoperative chemoradiation therapy in cervical cancer

Abstract

Neuropilin-1 expression identifies a subset of regulatory T cells in human lymph nodes that is modulated by preoperative chemoradiation therapy in cervical cancer Introduction CD4 + T cells that constitutively express the interleukin-2 (IL-2) receptor a-chain CD25 (regulatory T cells, Treg) and the master regulator Foxp3 transcription factor play a central and prominent role in maintaining self-tolerance and in regulating responses to infectious agents, transplantation antigens and tumour antigens. SummaryWe examined the phenotype and function of CD4 + T cells expressing the semaphorin III receptor neuropilin-1 (Nrp1) in human lymph nodes and peripheral blood. In lymph nodes, Nrp1 identified a small regulatory CD4 + CD25 high T-cell subpopulation (Nrp1 + Treg) that expressed higher levels of Forkhead box P3 (Foxp3) message and protein than Nrp1 ) Treg, and various molecular markers of activated Treg, i.e. CD45RO, human leucocyte antigen (HLA)-DR and glucocorticoid-induced tumour necrosis factor receptor (GITR). Similarly to conventional Treg, Nrp1 + Treg proliferated poorly in vitro, and exerted contact-dependent in vitro suppression of T-cell proliferation and cytokine secretion. However, Nrp1 + Treg were more efficient than Nrp1 ) Treg at inducing suppression. Nrp1 was also expressed on a small subpopulation of CD25 int and CD25 ) CD4 + T cells that expressed more Foxp3, CD45RO, HLA-DR and GITR than their Nrp1 ) counterparts. In contrast, in peripheral blood Nrp1 identified a minor CD4 + T-cell subset that did not display the phenotypic features of Treg lacking Foxp3 expression and marginally expressing CD25. Hence, the function of Nrp1 + CD4 + T cells seemingly depends on their anatomical location. In a previous report, we proposed that Treg may curb the anti-tumour T-cell response in cervical cancer. We show here that Treg and Nrp1 + Treg levels dropped in the tumour-draining lymph nodes of patients with cervical cancer following preoperative chemoradiotherapy in a direct relationship with the reduction of tumour mass, suggesting that suppressor cell elimination facilitated the generation of T cells mediating the destruction of the neoplastic cells left behind after cytotoxic therapy.

Density of Tumor-Infiltrating FOXP3+ T Cells as a Response Marker for Induction Chemoradiotherapy and a Potential Prognostic Factor in Patients Treated with Trimodality Therapy for Locally Advanced Non-Small Cell Lung Cancer

“…11,14,15) This result suggests that, to assess the response to induction CRT not only reduced tumor size or metabolic status of the tumor shown on CT or 18 F-deoxyglucose positron emission tomography but patient's immune response to the therapy also can be employed. Low tumor-infiltrating FOXP3+ Treg density was associated with favorable prognosis, although the difference was not statistically significant, as expected from its strong correlation with the pathological response and the impact of the pathological response on prognosis, suggesting that Tregs may be a possible target for adjunct immunotherapy.…”

“…In breast cancer patients treated with neoadjuvant chemotherapy, low infiltration of FOXP3+ Tregs with or without high CD8+ T cells was reported to be highly associated with good pathological response 11) or favorable prognosis. 12,13) Low FOXP3+ Treg density in the tumor stroma of ovarian cancer patients treated with neoadjuvant chemotherapy 14) or in the tumor-draining lymph nodes of patients with cervical cancer who underwent induction CRT 15) was also shown to be a favorable prognostic factor. To date, the effects of CRT on tumor-infiltrating T cells in patients with NSCLC are largely unknown.…”

Neuropilin‐1 is not a marker of human Foxp3+ Treg

“…Since two previous reports had identified Nrp-1-expressing T cells in human tonsils [14] and lymph nodes [15], we further analyzed our data focusing on such subsets. Nrp-1-expressing T cells were variably abundant in secondary lymphoid organs, but consistently rare in peripheral blood ( Fig.…”

HCV epitope, homologous to multiple human protein sequences, induces a regulatory T cell response in infected patients

“…This finding indicates that HCV_G1_p7_794 induces the conversion of conventional CD4 + FoxP3 -T cells to T reg cells, i.e., infectious tolerance, a suggestion supported by studies demonstrating the inability of nT reg cells to proliferate in response to their cognate antigen in vitro [34]. Furthermore, in contrast to Ab + VL + PBMCs cultured in medium alone, only a minority of CD3 + CD4 + FoxP3 + cells cultured in the presence of HCV_G1_p7_794 expressed CD304 (neuropilin), which is expressed by a subset of FoxP3 + T reg cells in humans and associated specifically with nT reg cells in mice [21,22]. While it has been suggested alternatively that the expanded T reg cell population in chronic, HCV infected patients is composed of cells phenotypically similar to nT reg or iT reg cells [11,20], our results concur with the consensus that the expanded T reg cell population in chronic HCV-infected patients is heterogeneous, composed of both T reg cell subsets.…”

“…CD304 (neuropilin-1) is expressed by a subset of FoxP3 + T reg cells in humans [21]. In mice, CD304 expression differentiates natural (CD304 + ), from inducible (CD304 -), T reg cells [22].…”