Ex vivo analysis of pancreatic cancer-infiltrating T lymphocytes reveals that ENO-specific Tregs accumulate in tumor tissue and inhibit Th1/Th17 effector cell functions
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Pancreatic cancer (PC) is an aggressive disease with dismal prognosis. Surgical resection is the recommended treatment for long-term survival, but patients with resectable PC are in the minority (with a 5-year survival rate of 20 %). Therefore, development of novel therapeutic strategies, such as anti-PC immunotherapy, is crucial. α-Enolase (ENO1) is an enzyme expressed on the surface of pancreatic cancer cells and is able to promote cell migration and cancer metastasis. The capacity of ENO1 to induce an immune response in PC patients renders it a true tumor-associated antigen. In this study, we characterized the effector functions of ENO1-specific T cells isolated from PC patients, and we specifically evaluated the successful role of intra-tumoral T helper 17 (Th17) cells and the inhibitory role of regulatory T (Tregs) cells in respectively promoting or reducing the cancer-specific immune response. In this ex vivo study, we have demonstrated, for the first time, that ENO1-specific Th17 cells have a specific anti-cancer effector function in PC patients, and that there are decreased levels of these cells in cancer compared to healthy mucosa. Conversely, there are elevated levels of ENO1-specific Tregs in PC patients which lead to inhibition of the antigen-specific effector T cells, thus highlighting a possible role in promoting PC progression. These results may be relevant for the design of novel immunotherapeutic strategies in pancreatic cancer.
KeywordsPancreatic cancer Tumor-infiltrating lymphocytes (TILs) Regulatory T cells (Tregs) T helper 17 (Th17) α-Enolase (ENO1)
This work is dedicated to the memory of Professor Gianfranco del Prete, who was a valuable researcher and teacher. We would like to thank Dr. Radhika Srinivasan for accurate editing of the manuscript. This work was supported by grants from the Italian Ministry of University and Research (PRIN 2009), the Italian Ministry of Health (Progetto Integrato Oncologia), the University of Florence, the Regione Piemonte (BIOTHER, IMMONC, Ricerca Sanitaria Finalizzata), the Associazione Italiana Ricerca sul Cancro (AIRC IG n. 11643 and 5 per 1000 n. 12182), the University of Torino-Progetti di Ateneo 2011 (grant Rethe-ORTO11RKTW), the Istituto Superiore di Sanità and European Community, the Seventh Framework Program, and the European Pancreatic Cancer-Tumor-Microenvironment Network (EPC-TM-Net, nr. 256974) and the Fondazione Internazionale di Medicina Sperimentale.
Conflict of interest
The authors declare that they have no conflict of interest.
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