Tropopoiitiko Fek

Research Team 10

Title: «Respiratory Immunity and Immunoregulation Team»

Supervisor: Maria Tsoumakidou

Current research and future outcomes:

Our team is actively looking to understand the role of pulmonary dendritic cells in lung cancer immune tolerance. The goal of our research is to ultimately come up with novel immunomodulatory agents that can be used in the clinic to abrogate tumor immune evasion. In this direction, we are currently phenotyping primary human lung tumors for a driver intracellular pathway common in cancer, i.e. the WNT pathway, with yet unkown function in tumor immunity. At the same time, five distinct types of primary human tumor-infiltrating antigen presenting cells are purified and their transriptomes analyzed by RNA sequencing. Then a systems biology approach is used to construct comprehensive network models that capture the interactions that operate between the Wnt pathway and intracellular tolerogenic circuits in antigen presenting cells. These theoretical models are functionally validated using experimental models of lung cancer immunity. Hence, we orthotopically engraft cancer cells in the lungs of syngeneic or congenic fully immunocompetent mice and gain detailed insight into tumor-specific T cell responses (phenotypic characterization, cytotoxicity assays, suppressive assays). To understand how tumor cells exploit common biological pathways to condition dendritic cells in favor of tumor tolerance, genetically engineered cancer cells are engrafted in reporter mice and dendritic cell-conditional knock-out mice.

In parallel studies, we are trying to elucidate the mechanistic links between COPD and lung cancer. Our working hypothesis is that cigarette smoke-induced chronic inflammation promotes lung cancer immune evasion by suppressing dendritic cells. Hence, we are analyzing how primary lung dendritic cells of COPD patients shape the extensive repertoire of cancer-specific T cell responses in ex vivo immunological assays. To validate these findings in vivo, we establish dual models of COPD and lung cancer and through adoptive transfer experiments of COPD lung DCs or COPD DC-primed T cells we follow in vivo the anti-tumor responses. Along the above experimental lines, we obtain high throughput data of the proteomic profile of the COPD microenvironment and of the transcriptional profile of lung dendritic cells and we integrate these data, to construct a model that captures the interactions that operate between environmental signals and intracellular circuits in dendritic cells. We then go ahead and target inflammatory molecules as potential therapy for COPD-associated lung cancer.

Representative Publications:

Tolerogenic signaling by pulmonary CD1c+ dendritic cells induces regulatory T cells in patients with chronic obstructive pulmonary disease by IL-27/IL-10/inducible costimulator ligand. Tsoumakidou M, Tousa S, Semitekolou M, Panagiotou P, Panagiotou A, Morianos I, Litsiou E, Trochoutsou AI, Konstantinou M, Potaris K, Footitt J, Mallia P, Zakynthinos S, Johnston SL, Xanthou G. J Allergy Clin Immunol. 2014 Oct;134(4):944-954.

CXCL13 production in B cells via Toll-like receptor/lymphotoxin receptor signaling is involved in lymphoid neogenesis in chronic obstructive pulmonary disease. Litsiou E, Semitekolou M, Galani IE, Morianos I, Tsoutsa A, Kara P, Rontogianni D, Bellenis I, Konstantinou M, Potaris K, Andreakos E, Sideras P, Zakynthinos S, Tsoumakidou M. Am J Respir Crit Care Med. 2013 Jun 1;187(11):1194-202.

Dendritic cells in chronic obstructive pulmonary disease: new players in an old game. Tsoumakidou M, Demedts IK, Brusselle GG, Jeffery PK. Am J Respir Crit Care Med. 2008 Jun 1;177(11):1180-6.

Cigarette smoking alters bronchial mucosal immunity in asthma. Tsoumakidou M, Elston W, Zhu J, Wang Z, Gamble E, Siafakas NM, Barnes NC, Jeffery PK. Am J Respir Crit Care Med. 2007 May 1;175(9):919-25.