Purpose: Tumor-infiltrating lymphocytes (TIL), in particular CD8þ T cells and CD20 þ B cells, are strongly associated with survival in ovarian cancer and other carcinomas. Although CD8 þ TIL can mediate direct cytolytic activity against tumors, the role of CD20 þ TIL is poorly understood. Here, we investigate the possible contributions of CD20 þ TIL to humoral and cellular tumor immunity.Experimental Design: Tumor and serum specimens were obtained from patients with high-grade serous ovarian cancer. CD8þ and CD20 þ TIL were analyzed by immunohistochemistry and flow cytometry.Immunoglobulin molecules were evaluated by DNA sequencing. Serum autoantibody responses to the tumor antigens p53 and NY-ESO-1 were measured by ELISA.Results: The vast majority of CD20 þ TIL were antigen experienced, as evidenced by class-switching, somatic hypermutation, and oligoclonality, yet they failed to express the canonical memory marker CD27. CD20 þ TIL showed no correlation with serum autoantibodies to p53 or NY-ESO-1. Instead, they colocalized with activated CD8 þ TIL and expressed markers of antigen presentation, including MHC class I, MHC class II, CD40, CD80, and CD86. The presence of both CD20 þ and CD8 þ TIL correlated with increased patient survival compared with CD8 þ TIL alone. Conclusions:In high-grade serous ovarian tumors, CD20 þ TIL have an antigen-experienced but atypical CD27 À memory B-cell phenotype. They are uncoupled from serum autoantibodies, express markers of antigen-presenting cells, and colocalize with CD8 þ T cells. We propose that the association between CD20 þ TIL and patient survival may reflect a supportive role in cytolytic immune responses.
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.
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