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, Gilberto Filaci

Research output: Contribution to journalArticle

Abstract

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 (IFN?+ 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 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.

Original languageEnglish
Pages (from-to)6424-6435
Number of pages12
JournalOncotarget
Volume7
Issue number6
DOIs
Publication statusPublished - 2016

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Keywords

  • Bladder cancer
  • Immune response
  • Immunity
  • Immunology and microbiology section
  • Mage
  • Th1
  • Th17
  • Tumor infiltrating lymphocytes

ASJC Scopus subject areas

  • Oncology

Cite this

Parodi, A., Traverso, P., Kalli, F., Conteduca, G., Tardito, S., Curto, M., Grillo, F., Mastracci, L., Bernardi, C., Nasi, G., Minaglia, F., Simonato, A., Carmignani, G., Ferrera, F., Fenoglio, D., & Filaci, G. (2016). Residual tumor micro-foci and overwhelming regulatory T lymphocyte infiltration are the causes of bladder cancer recurrence. Oncotarget, 7(6), 6424-6435. https://doi.org/10.18632/oncotarget.7024