Research Papers: Immunology:

Residual tumor micro-foci and overwhelming regulatory T lymphocyte infiltration are the causes of bladder cancer recurrence

Alessia Parodi, Paolo Traverso, Francesca Kalli, Giuseppina Conteduca, Samuele Tardito, Monica Curto, Federica Grillo, Luca Mastracci, Cinzia Bernardi, Giorgia Nasi, Francesco Minaglia, Alchiede Simonato, Giorgio Carmignani, Francesca Ferrera, Daniela Fenoglio and Gilberto Filaci _

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Oncotarget. 2016; 7:6424-6435. https://doi.org/10.18632/oncotarget.7024

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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

Correspondence to:

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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