The Prognostic Value of FoxP3+ Tumor-Infiltrating Lymphocytes in Cancer: A Critical Review of the Literature

Abstract

CD8þ tumor-infiltrating lymphocytes (TIL) are associated with survival in a variety of cancers. A second subpopulation of TIL, defined by forkhead box protein P3 (FoxP3) expression, has been reported to inhibit tumor immunity, resulting in decreased patient survival. On the basis of this premise, several groups are attempting to deplete FoxP3þ T cells to enhance tumor immunity. However, recent studies have challenged this paradigm by showing that FoxP3þ T cells exhibit heterogeneous phenotypes and, in some cohorts, are associated with favorable prognosis. These discrepant results could arise from differences in study methodologies or the biologic properties of specific cancer types. Here, we conduct the first systematic review of the prognostic significance of FoxP3þ T cells across nonlymphoid cancers (58 studies from 16 cancers). We assessed antibody specificity, cell-scoring strategy, multivariate modeling, use of single compared with multiple markers, and tumor site. Two factors proved important. First, when FoxP3 was combined with one additional marker, double-positive T cells were generally associated with poor prognosis. Second, tumor site had a major influence. FoxP3þ T cells were associated with poor prognosis in hepatocellular cancer and generally good prognosis in colorectal cancer, whereas other cancer types were inconsistent or understudied. We conclude that FoxP3þ T cells have heterogeneous properties that can be discerned by the use of additional markers. Furthermore, the net biologic effects of FoxP3þ T cells seem to depend on the tumor site, perhaps reflecting microenvironmental differences. Thus, depletion of FoxP3þ T cells might enhance tumor immunity in some patient groups but be detrimental in others.

Tumor-Infiltrating Regulatory T Cells: Phenotype, Role, Mechanism of Expansion In Situ and Clinical Significance

“…Such a good prognostic value of Tregs in head and neck cancer has subsequently been confirmed by others [98,99] and extended to additional solid neoplasms including colorectal carcinoma [100,101] and bladder cancer [102]. In some tumor types including hepatocellular carcinoma and breast cancer, high levels of intratumoral Tregs have been clearly associated with bad prognosis, whereas in other types such as colorectal cancer, head and neck carcinoma and lymphoma, robust tumor infiltration by Tregs frequently correlates with improved disease outcome [103,104].…”

“…In particular, a high CD8 + Teff/Treg ratio has been associated with favorable disease outcome in ovarian and hepatocellular carcinoma patients [93,115] and with a poor prognosis in subjects affected by head and neck cancer [116]. Of note, while in some studies, the prognostic value of Tregs seems to be influenced by tumor stage [29,117], results from a recent meta-analysis indicate that tumor stage does not account for the variations of FOXP3 prognostic performance [104].…”

Therapeutic DC vaccination with IL-2 as a consolidation therapy for ovarian cancer patients: a phase I/II trial

“…23 In the present study, the DC vaccine reduced the proportion of CD41CD25 high cells without a significant correlation with other immune parameters or clinical responses (Tables 2 and 3). In the present study, CD4 25 reviewed the controversial role of regulatory T cells in cancer prognosis, suggesting an anti-tumor effect of Foxp3 1 Tregs through the inhibition of inflammatory cells. In the absence of T cell subset markers, such as CD4 1 , Foxp3 expression alone might not be sufficient to identify functionally homogeneous Tregs that inhibit anti-tumor immunity.…”

Implications of NOVA1 suppression within the microenvironment of gastric cancer: association with immune cell dysregulation

“…The prognostic value of infiltrating FOXP3 ? Tregs in the cancer microenvironment is inconsistent, and they are associated with poor prognosis or good prognosis in various cancer types, including gastric cancers [17,18]. In the present study, the lower number of infiltrating FOXP3 ?…”

“…Staining intensity (1, no staining to weak intensity; 2, moderate intensity; 3, strong intensity) was multiplied by the percentage of positive cell nuclei (1, 0-9 %; 2, 10-19 %; 3, 20-29 %; 4, 30-39 %; 5, 40-49 %; 6, 50-59 %; 7, 60-69 %; 8, 70-79 %; 9, 80-89 %; 10, 90-100 %). NOVA1 expression was scored from 1 to 30 and classified as strong (score 21-30), moderate (score [11][12][13][14][15][16][17][18][19][20], or weak (score 1-10). The expression pattern of NOVA1 was evaluated in tumor cells, stromal spindle cells (fibroblasts, support cells, and endothelial cells), and immune cells (Fig.…”