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Inhibition of Human Tumor-Infiltrating Lymphocyte Effector Functions by the Homophilic Carcinoembryonic Cell Adhesion Molecule 1 Interactions¹

Gal Markel^2,*, Rachel Seidman^*, Noam Stern, Tali Cohen-Sinai^*, Orit Izhaki^*, Gil Katz, Michal Besser^*, Avraham J. Treves^*, Richard S. Blumberg, Ron Loewenthal, Ofer Mandelboim, Arie Orenstein^¶ and Jacob Schachter^*

^* Ella Institute for Melanoma Research and Treatment, Sheba Cancer Research Center, Sheba Medical Center, Tel-Hashomer, Israel; Lautenberg Center for General and Tumor Immunology, Hadassah Medical School, Jerusalem, Israel; Division of Gastroenterology, Brigham and Women’s Hospital, Boston, MA 02115; Tissue Typing Laboratory, Sheba Medical Center, Tel-Hashomer, Israel; and ^¶ Institute of Advanced Technologies, Sheba Medical Center, Tel-Hashomer, Israel

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- 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.

The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ G.M. is supported by the Sheba Researcher-Physician Fund, Israel Cancer Association, and Israel Cancer Research Fund.

² Address correspondence and reprint requests to Dr. Gal Markel, Ella Institute for Melanoma Research and Treatment, Sheba Cancer Research Center, Sheba Medical Center, Tel-Hashomer 52621, Israel. E-mail address: gal.markel{at}gmail.com

³ Abbreviations used in this paper: ACT, adoptive cellular transfer; TIL, tumor-infiltrating lymphocyte; CEACAM1, carcinoembryonic Ag cell adhesion molecule; MCSP, melanoma-associated chondroitin sulfate proteoglycan; PI, propidium iodide; MFI, median fluorescence intensity.

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