Background Regulatory FoxP3+ lymphocytes function as suppressors of T-cell activity. The clinical impact of high FoxP3+ cell density in cancers is not fully understood, as some studies have linked high FoxP3+ cell density to good prognosis and others to poor prognosis in tumor cohorts with associated clinical data. While some data suggest that these variable data are due to biological differences between tumor entities, it is also possible that methodological differences have caused these discrepancies. This study was undertaken to analyze the density of FoxP3+ cells in various different cancer types by employing standardized methods.
Materials and Methods Tissue microarrays and large sections made from >20,000 prostate, breast, colorectal, ovarian, pancreatic, bladder and stomach cancers were analyzed together with various normal and inflamed tissues by conventional brightfield FoxP3 immunohistochemistry. Samples were also analyzed by fluorescent multiplex immunohistochemistry to assess the fraction of Ki67+ FoxP3+ cells.
Results Our results indeed suggested a variable role of FoxP3+ cells in different tumor types. High FoxP3+ density was linked to high Gleason grade (p=0.0003) and early biochemical recurrence (p<0.0001) in 16923 prostate cancers, but to low tumor stage (p=0.027) and prolonged survival (p=0.0029) in 1341 breast cancers, and to low tumor stage (p<0.0001) in 744 colorectal cancers. No significant associations were found to tumor phenotype in 549 ovarian, 574 pancreatic, 549 bladder and 346 stomach cancers. Multiplex fluorescence IHC analysis of FoxP3 and Ki67 revealed comparable fractions of proliferating FoxP3+ cells in healthy tissues (average 12.3%, range 5.8–18.5%) and inflammatory conditions (average 7.6%, range 2.6–17.2%). Interestingly, the rate of Ki67+FoxP3+ cells was markedly higher in 36 bladder cancers (average 14.2%, range 0–49.3%) suggesting active expansion of FoxP3+ cells in cancer.
Conclusions Our data demonstrate an inverse prognostic impact of the FoxP3+ cell density in prostate and breast cancers. The increased proliferation rate of immune-regulatory FoxP3+ cells in some bladder cancer is interesting in the light of the variable response of these tumors to immune checkpoint inhibitors.
Disclosure Information T. Mandelkow: None. E. Bady: None. N.C. Blessin: None. C. Hube-Magg: None. R. Simon: None. G. Sauter: None. C. Fraune: None. M. Lennartz: None. K. Möller: None. S.A. Weidemann: None. A.M. Luebke: None. D. Höflmayer: None. F. Büscheck: None.