The immunomodulatory molecule TIGIT is expressed by chronic lymphocytic leukemia cells and contributes to anergy
Francesca Arruga,
Marta Rubin,
Despoina Papazoglou,
Andrea Iannello,
Nikolaos Ioannou,
Riccardo Moia,
Davide Rossi,
Gianluca Gaidano,
Marta Coscia,
Luca Laurenti,
Giovanni D’Arena,
John N. Allan,
Richard R. Furman,
Tiziana Vaisitti,
Alan G. Ramsay,
Silvia Deaglio
Affiliations
Francesca Arruga
Laboratory of Functional Genomics, Department of Medical Sciences, University of Turin, Turin
Marta Rubin
Laboratory of Functional Genomics, Department of Medical Sciences, University of Turin, Turin
Despoina Papazoglou
School of Cancer and Pharmaceutical Sciences, King’s College London, London
Andrea Iannello
Laboratory of Functional Genomics, Department of Medical Sciences, University of Turin, Turin
Nikolaos Ioannou
School of Cancer and Pharmaceutical Sciences, King’s College London, London
Riccardo Moia
Division of Hematology, Department of Translational Medicine, University of Eastern Piedmont, Novara
Davide Rossi
Laboratory of Experimental Hematology, Institute of Oncology Research; Faculty of Biomedical Sciences, Universita della Svizzera Italiana
Gianluca Gaidano
Division of Hematology, Department of Translational Medicine, University of Eastern Piedmont, Novara
Marta Coscia
Department of Molecular Biotechnology and Health Sciences, University of Turin and Division of Hematology, A.O.U. Citta della Salute e della Scienza di Torino, Turin
Luca Laurenti
Hematology Unit, IRCCS Fondazione Policlinico Gemelli, Catholic University of "Sacred Heart", Rome
Giovanni D’Arena
Hematology, P.O. "S. Luca", ASL Salerno, Salerno
John N. Allan
Department of Hematology, Weill Cornell Medicine, New York, NY
Richard R. Furman
Department of Hematology, Weill Cornell Medicine, New York, NY
Tiziana Vaisitti
Laboratory of Functional Genomics, Department of Medical Sciences, University of Turin, Turin
Alan G. Ramsay
School of Cancer and Pharmaceutical Sciences, King’s College London, London
Silvia Deaglio
Laboratory of Functional Genomics, Department of Medical Sciences, University of Turin, Turin
T-cell immunoreceptor with Ig and ITIM domains (TIGIT) is an inhibitory checkpoint receptor that negatively regulates Tcell responses. CD226 competes with TIGIT for binding to the CD155 ligand, delivering a positive signal to the T cell. Here we studied the expression of TIGIT and CD226 in a cohort of 115 patients with chronic lymphocytic leukemia (CLL) and report expression of TIGIT and CD226 by leukemic cells. By devising a TIGIT/CD226 ratio, we showed that CLL cells favoring TIGIT over CD226 are typical of a more indolent disease, while those favoring CD226 are characterized by a shorter time to first treatment and shorter progression-free survival after first treatment. TIGIT expression was inversely correlated to the B-cell receptor (BCR) signaling capacity, as determined by studying BTK phosphorylation, cell proliferation and interleukin- 10 production. In CLL cells treated with ibrutinib, in which surface IgM and BCR signaling capacity are temporarily increased, TIGIT expression was downmodulated, in line with data indicating transient recovery from anergy. Lastly, cells from patients with Richter syndrome were characterized by high levels of CD226, with low to undetectable TIGIT, in keeping with their high proliferative drive. Together, these data suggest that TIGIT contributes to CLL anergy by downregulating BCR signaling, identifying novel and actionable molecular circuits regulating anergy and modulating CLL cell functions.
