Abstract
In the present study, we evaluated tumor-infiltrating lymphocytes (TILs) and blood regulatory T lymphocyte (Tregs, CD4+/CD25+/FoxP3+) expression in bladder cancer patients. The number of CD4+, CD8+, CD25+, FoxP3+ and CD20+ TILs was analyzed in association with clinico-pathomorphological features. In more advanced metastasizing tumors, showing non-classic differentiation (ND) and a more aggressive tissue invasion type (TIT), the number of TILs decreased. A low number of CD4+ TILs was associated with poor prognosis. Similarly, Treg frequency before surgery and after surgical treatment was significantly lower in more advanced tumors. The changes in TILs, as well as of local and systemic Tregs, were accompanied by changes in the histological phenotype of urothelial carcinoma regarding pT stage, NDs, TIT, and clinical outcomes. The number of TILs and the frequency of blood Tregs (indicators of antitumor response) may be essential for choosing an immunotherapy that is adjusted to the immune status according to the phase of tumor growth. Moreover, a significant reduction in the number of CD4+ and CD8+ TILs with the development of NDs in more advanced tumors may be associated with lower tumor immunogenicity, resulting in immune tolerance towards tumor tissue. These observations and the tendency of urothelial bladder carcinoma to undergo NDs in a heterogeneous manner during tumor progression suggest complex interactions between bladder cancer immunogenicity and stages of tumor progression.
Highlights
The prognosis of urothelial carcinoma of the urinary bladder is determined by the tumor stage and its pathological features ([1,2,3], reviewed in [4])
We found that the number of CD4+, CD8+, CD25+, FoxP3+ and CD20+ tumor-infiltrating lymphocytes (TILs) and the frequency of blood Tregs changed with the progression of the urinary bladder cancer
Changes in the representation of effector cells and local (TILs) and systemic Tregs were accompanied by changes in the histological phenotype of urothelial carcinoma in relation to pT stage, non-classic differentiation number (NDN), the type of tissue invasion, and clinical outcomes such as metastasis and patients’ death
Summary
The prognosis of urothelial carcinoma of the urinary bladder is determined by the tumor stage and its pathological features ([1,2,3], reviewed in [4]). Defining histological and clinical indicators of malignancy enabled better characterization of the neoplastic progression in bladder cancer. Tumors at pT2–pT4 exhibit a more aggressive tissue invasion type (TIT) compared with pT1 tumors), which are limited to the mucosa and the submucosa of the urinary bladder wall. Our previous research has indicated that histological and clinical markers of urothelial carcinoma of the bladder correlate with molecular events suggesting a complex pathomechanism of bladder cancer malignancy [5,6,7]. ROfuarce antigen) previous research has indicated that histological and clinical markers of urothelial carcinoma of the expressionblainddnereocoprlraelsattiecwciethllsmoolreciunlatruemveonrtsmsuigcgreosetinngviaroconmmpelenxtpcaethllosmienchdainciastmesofthbleadtduemr coarnceesrcape from immune smuravligenilalnacnyc[e5–d7]u. Expression of stem cell markers was related to poor prognosis in other tumors [8–d1if0fe]r.eWntieathioanv, ewhailcshoisshcoonwnencttehdawt iRthCtAheSd1ev(reelocpempetnotr-obf itnhde ianbgilitcyatnocmere-taasstsaosicziea[t1e–d3,6s]u. rOfuarce antigen) previous research has indicated that histological and clinical markers of urothelial carcinoma of the expressionblainddnereocoprlraelsattiecwciethllsmoolreciunlatruemveonrtsmsuigcgreosetinngviaroconmmpelenxtpcaethllosmienchdainciastmesofthbleadtduemr coarnceesrcape from immune smuravligenilalnacnyc[e5–d7]u. rTihnagt smtuadlyigsnhoawnetdphroigghreer srseiporense[n1t1a]ti.oSniomf itluamrloyr, OinCTp4a+ticeenllsts(twheitshtemovcaerllian cancer who did npohtenreostyppoe)nwdatsoastshoecriaatepdy,waithsitgunmiofircparnogtlryeshsioignhdeerfineexdparsesinsviaosnioonfofRmCuAcoSs1a (wthiethfiirnst bstoagthe),the cancer cells and mitnhfiiricldtrroastteaiongnev)oi[rf7ot]h.neSmimmeuinlsatcralleyl,lTaeyxAeprMreossfsito(htneuobmflasodtred-mearscwseolallclmi(atahtreekdesresmcownaadcsrsroteaplaghtee)ad, gatneodsp)moooerrtapCsrtaoAtgiFnc ospsr(iosccaiennssoct(ehtrheerassociated fibroblastst)umwoarss [o8b–1s0e]r. vWeedhianvecaolsmo pshaorwisnotnhattoRpCAatSi1en(rtescewpthoro-briendspinogncdanecder-taosstohceiatterdeasutmrfaecnetan[1ti2g]e.n)
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