Regulatory T Cells in Ovarian Cancer Are Characterized by a Highly Activated Phenotype Distinct from that in Melanoma

Abstract

Regulatory T (Treg) cells expressing the transcription factor FOXP3 are essential for the maintenance of immunologic self-tolerance but play a detrimental role in most cancers due to their ability to suppress antitumor immunity. The phenotype of human circulating Treg cells has been extensively studied, but less is known about tumor-infiltrating Treg cells. We studied the phenotype and function of tumor-infiltrating Treg cells in ovarian cancer and melanoma to identify potential Treg cell-associated molecules that can be targeted by tumor immunotherapies. The phenotype of intratumoral and circulating Treg cells was analyzed by multicolor flow cytometry, mass cytometry, RNA-seq, and functional assays. Treg cells isolated from ovarian tumors displayed a distinct cell surface phenotype with increased expression of a number of receptors associated with TCR engagement, including PD-1, 4-1BB, and ICOS. Higher PD-1 and 4-1BB expression was associated with increased responsiveness to further TCR stimulation and increased suppressive capacity, respectively. Transcriptomic and mass cytometry analyses revealed the presence of Treg cell subpopulations and further supported a highly activated state specifically in ovarian tumors. In comparison, Treg cells infiltrating melanomas displayed lower FOXP3, PD-1, 4-1BB, and ICOS expression and were less potent suppressors of CD8 T-cell proliferation. The highly activated phenotype of ovarian tumor-infiltrating Treg cells may be a key component of an immunosuppressive tumor microenvironment. Receptors that are expressed by tumor-infiltrating Treg cells could be exploited for the design of novel combination tumor immunotherapies. .

Analysis of the treg cell population in the peripheral blood of ovarian cancer patients in relation to the long-term outcomes

“…Furthermore, Toker et al demonstrated that the Treg cells that infiltrate the ovarian cancer nest are typified by a distinct surface phenotype that differs from the ones found in other types of cancer nests. These cells are characterized by an increased expression of PD-1 and 4-1BB, both of which are associated with an increased suppressive capacity [25]. Additionally, Curiel et al reported that, in the later stages of cancer, Treg cells seem to have a preference towards tumors and ascites and will only rarely accumulate in the draining lymph nodes [11].…”

Contribution of regulatory T cells to cancer: A review

“…TCR inhibition could cause a decrease in the rate of proliferation and impaired functioning in the cells (Y. . (Toker et al, 2018). This reprogramming is applicable through suppressing receptor/ligand interactions for CD25, neuropilin-1 (Nrp-1), and FOXP3 expressed on Tregs.…”

Highly immunosuppressive HLADRhi regulatory T cells are associated with unfavorable outcomes in cervical squamous cell carcinoma

“…2 Treg cells are characterized by the expression of the key transcription factor forkhead box protein 3 (Foxp3), 4 which is essential for maintaining self-tolerance and immune homeostasis. [4][5][6] Treg cells have also been reported in cervical cancer, particularly CSCC; these studies have mostly dealt with Tregs as a whole population and the associated clinical consequences. [4][5][6] Treg cells have also been reported in cervical cancer, particularly CSCC; these studies have mostly dealt with Tregs as a whole population and the associated clinical consequences.…”

“…2,3 Accumulating data have suggested that the progression from HPV infection to (pre)neoplastic lesions is associated with altered local immune responses, which makes cervical cancer an important immunogenic cancer. 2 Treg cells are characterized by the expression of the key transcription factor forkhead box protein 3 (Foxp3), 4 which is essential for maintaining self-tolerance and immune homeostasis. 3 In addition, an increased prevalence of Treg cells in both peripheral blood and tumor tissues has been observed in patients with various cancers.…”

“…3 In addition, an increased prevalence of Treg cells in both peripheral blood and tumor tissues has been observed in patients with various cancers. [4][5][6] Treg cells have also been reported in cervical cancer, particularly CSCC; these studies have mostly dealt with Tregs as a whole population and the associated clinical consequences. [7][8][9][10][11][12][13][14] It has been gradually recognized that Tregs are more heterogeneous than originally thought, consisting of phenotypically and functionally diverse subpopulations.…”