title: Inhibition of human tumor-infiltrating lymphocyte effector functions by the homophilic carcinoembryonic cell adhesion molecule 1 interactions.
abstract: Efficient antitumor immune response requires the coordinated function of integrated immune components, but is finally exerted by the differentiated effector tumor-infiltrating lymphocytes (TIL). TIL cells comprise, therefore, an exciting platform for adoptive cell transfer (ACT) in cancer. In this study, we show that the inhibitory carcinoembryonic Ag cell adhesion molecule 1 (CEACAM1) protein is found on virtually all human TIL cells following preparation protocols of ACT treatment for melanoma. We further demonstrate that the CEACAM1 homophilic interactions inhibit the TIL effector functions, such as specific killing and IFN-gamma release. These results suggest that CEACAM1 may impair in vivo the antitumor response of the differentiated TIL. Importantly, CEACAM1 is commonly expressed by melanoma and its presence is associated with poor prognosis. Remarkably, the prolonged coincubation of reactive TIL cells with their melanoma targets results in increased functional CEACAM1 expression by the surviving tumor cells. This mechanism might be used by melanoma cells in vivo to evade ongoing destruction by tumor-reactive lymphocytes. Finally, CEACAM1-mediated inhibition may hinder in many cases the efficacy of TIL ACT treatment of melanoma. We show that the intensity of CEACAM1 expression on TIL cells constantly increases during ex vivo expansion. The implications of CEACAM1-mediated inhibition of TIL cells on the optimization of current ACT protocols and on the development of future immunotherapeutic modalities are discussed.
authors.affiliation: Ella Institute for Melanoma Research and Treatment, Sheba Cancer Research Center, Sheba Medical Center, Tel-Hashomer 52621, Israel. gal.markel@gmail.com
authors.forename: Gal
authors.initials: G
authors.lastname: Markel
authors.forename: Rachel
authors.initials: R
authors.lastname: Seidman
authors.forename: Noam
authors.initials: N
authors.lastname: Stern
authors.forename: Tali
authors.initials: T
authors.lastname: Cohen-Sinai
authors.forename: Orit
authors.initials: O
authors.lastname: Izhaki
authors.forename: Gil
authors.initials: G
authors.lastname: Katz
authors.forename: Michal
authors.initials: M
authors.lastname: Besser
authors.forename: Avraham J
authors.initials: AJ
authors.lastname: Treves
authors.forename: Richard S
authors.initials: RS
authors.lastname: Blumberg
authors.forename: Ron
authors.initials: R
authors.lastname: Loewenthal
authors.forename: Ofer
authors.initials: O
authors.lastname: Mandelboim
authors.forename: Arie
authors.initials: A
authors.lastname: Orenstein
authors.forename: Jacob
authors.initials: J
authors.lastname: Schachter
mesh_terms: D000818:Animals; D015703:Antigens, CD / Q000032:analysis / Q000235:genetics / Q000378:metabolism*; D015815:Cell Adhesion Molecules / Q000032:analysis / Q000235:genetics / Q000378:metabolism*; D045744:Cell Line, Tumor; D002470:Cell Survival; D018920:Coculture Techniques; D003602:Cytotoxicity, Immunologic; D006801:Humans; D016246:Lymphocytes, Tumor-Infiltrating / Q000737:chemistry / Q000276:immunology*; D008545:Melanoma / Q000276:immunology* / Q000378:metabolism; D051379:Mice; D015854:Up-Regulation
chemical_list: D015703:Antigens, CD; C069847:CD66 antigens; D015815:Cell Adhesion Molecules