Research Papers: Immunology:
Residual tumor micro-foci and overwhelming regulatory T lymphocyte infiltration are the causes of bladder cancer recurrence
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Alessia Parodi1,*, Paolo Traverso1,2,3,*, Francesca Kalli1, Giuseppina Conteduca1, Samuele Tardito1, Monica Curto1, Federica Grillo2,3, Luca Mastracci2,3, Cinzia Bernardi1, Giorgia Nasi1, Francesco Minaglia2,3, Alchiede Simonato2,3, Giorgio Carmignani2,3, Francesca Ferrera1, Daniela Fenoglio1,3,4 and Gilberto Filaci1,3,4
1 Centre of Excellence for Biomedical Research, University of Genoa, Genoa, Italy
2 Department of Surgical Sciences and Integrated Diagnostics, University of Genoa, Genoa, Italy
3 IRCCS Azienda Ospedaliero Universitaria San Martino – IST - Istituto Nazionale per la Ricerca sul Cancro, Genoa, Italy
4 Department of Internal Medicine, University of Genoa, Genoa, Italy
* These authors have contributed equally to this work
Gilberto Filaci, email:
Keywords: bladder cancer, tumor infiltrating lymphocytes, MAGE, Th1, Th17, Immunology and Microbiology Section, Immune response, Immunity
Received: September 21, 2015 Accepted: January 02, 2016 Published: January 25, 2016
Bladder cancer has an unexplained, high recurrence rate. Causes of recurrence might include the presence of sporadic tumor micro-foci in the residual urothelial tissue after surgery associated with an inverted ratio between intratumoral effector and regulatory T cell subsets. Hence, surgical specimens of both tumors and autologous, macroscopically/histologically free-of-tumor tissues were collected from 28 and 20 patients affected by bladder or renal cancer, respectively. The frequencies of effector (IFNγ+ and IL17+ T cells) and regulatory (CD4+CD25hiCD127lo and CD8+CD28-CD127loCD39+ Treg) T cell subpopulations among tumor infiltrating lymphocytes were analyzed by immunofluorescence, while the gene expression of MAGE-A1 and MAGE-A2 tumor-associated antigens was studied by RT-PCR. The results show that both the T cell infiltrate and the frequency of MAGE-A1/A2 gene expression were comparable in tumors and in autologous free-of-tumor tissues in bladder cancer, while the autologous free-of-tumor renal tissues showed reduced T cell infiltrate and frequency of MAGE gene expression as compared to the autologous tumors. Importantly, the intra-tumor T effector/Treg cell ratio was consistently <1 in bladder cancer patients (n. 7) who relapsed within two years, while it was always >1 in patients (n. 6) without recurrence (regardless of tumor stage) (P = 0.0006, Odds ratio = 195). These unprecedented findings clarify the pathogenic mechanism of bladder cancer recurrence and suggest that microscopically undetectable micro-foci of tumor may predispose to recurrence when associated with an inverted intratumoral T effector/Treg cell ratio.
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