Sialyl-Tn antigen (STn), which covers bladder cancer cells, contributes to the immune escape of these cells

Tumor cells often have aberrant post-translational modifications of their proteins. In bladder cancer, one of these modifications is the sialyl-Tn (STn) glycan, which is not expressed by normal cells and is highly expressed in high-grade bladder cancer cells. It is known that the immune response is affected by tumor cells, promoting tumor progression. However, little is known about the role of STn in the immune response and its influence on immune cells. Dendritic cells (DCs) play a crucial role in the immune response against tumor cells. They are able to capture tumor antigens and, when mature, specifically activate T lymphocytes against tumor cells, leading to the tumor death. However, DCs may lose that ability under the influence of tumor cells and, in this case, promote tumor progression. In this study, we were able to better understand the role of the STn glycan expressed by bladder cancer cells in DCs immune response. It was found that the presence of STn is directly correlated with the presence of immature DCs in tumor tissue. Using a bladder cancer cell line transduced to express STn, we proved that the presence of STn in tumor cells induced a lower DCs maturation and costimulation, leading to a reduced ability to activate T lymphocytes. Thus, we have demonstrated that the STn antigen is responsible for influencing DCs to become tolerogenic, protecting tumor cells from anti-tumor responses. This study showed that STn is a potential therapeutic target for overcoming tumor immune escape mechanisms. This study was supported by Prémio Santander-Totta/UNL and LPCC/Pfizer2011.

Authors and Affiliations:

Mylène A. Carrascal1, Paulo F. Severino1,2, M. Guadalupe Cabral1,3, Mariana Silva1, José Alexandre Ferreira4,5, Fernando Calais6, Hermínia Quinto6, Cláudia Pen6, Dário Ligeiro7, Lúcio Lara Santos5,8, Fabio Dall’Olio2, Paula A. Videira1

1CEDOC, Faculdade de Ciências Médicas, Universidade NOVA de Lisboa, Lisbon, Portugal

2Department of Experimental, Clinical and Specialty Medicine (DIMES), University of Bologna, Bologna, Italy

3Faculdade de Engenharia, Universidade Lusófona de Humanidades e Tecnologias, Lisbon, Portugal

4QOPNA, Mass Spectrometry Center, Department of Chemistry, University of Aveiro, Aveiro, Portugal

5Experimental Pathology and Therapeutics Group, Portuguese Institute of Oncology, Porto, Portugal

6Centro Hospitalar de Lisboa Central, EPE e Serviço de Anatomia Patológica, Lisbon, Portugal

7Centro de Histocompatibilidade do Sul, Lisboa, Portugal

8Department of Surgical Oncology, Portuguese Institute of Oncology, Porto, Portugal

Abstract:

Despite the wide acceptance that glycans are centrally implicated in immunity, exactly how they contribute to the tilt immune response remains poorly defined. In this study, we sought to evaluate the impact of the malignant phenotype-associated glycan, sialyl-Tn (STn) in the function of the key orchestrators of the immune response, the dendritic cells (DCs). In high grade bladder cancer tissue, the STn antigen is significantly overexpressed and correlated with the increased expression of ST6GALNAC1 sialyltransferase. Bladder cancer tissue presenting elevated expression of ST6GALNAC1 showed a correlation with increased expression of CD1a, a marker for bladder immature DCs and showed concomitant low levels of Th1-inducing cytokines IL-12 and TNF-a. In vitro, human DCs co-incubated with STn+ bladder cancer cells, had an immature phenotype (MHC-II^low, CD80^low and CD86^low) and were unresponsive to further maturation stimuli. When contacting with STn+ cancer cells, DCs expressed significantly less IL-12 and TNF-a. Consistent with a tolerogenic DC profile, T cells that were primed by DCs pulsed with antigens derived from STn+ cancer cells were not activated and showed a FoxP3high IFN-glow phenotype. Blockade of STn antigens and of STn+ glycoprotein, CD44 and MUC1, in STn+ cancer cells was able to lower the induction of tolerance and DCs become more mature. Overall, our data suggest that STn-expressing cancer cells impair DC maturation and endow DCs with a tolerogenic function, limiting their capacity to trigger protective antitumour T cell responses. STn antigens and, in particular, STn+ glycoproteins are potential targets for circumventing tumour-induced tolerogenic mechanisms.

Journal:

Molecular Oncology

Link:

http://www.sciencedirect.com/science/article/pii/S1574789114000477