Abstract LB-142: CD94/NKG2A+ tumor-infiltrating lymphocytes in a context of HLA-E overexpression could be a promising new druggable inhibitory immune checkpoint in colorectal adenocarcinomas
Authors: EUGENE Juliette , JOUAND Nicolas , DANSETTE Delphine , MEURETTE Guillaume , Podevin Juliette , MATYSIAK Tamara , BEZIEAU Stephane , VOLTEAU Christelle , THOMAS Wassila EL ALAMI , CHETRITT Jerome , KERDRAON Olivier , Fourquier Pierre , THIBAUDEAU Emilie , DUMONT Frederic , MOSNIER Jean-Francois , TOQUET Claire , JARRY Anne , GERVOIS Nadine , Bossard Celine 
Published: August 2018

Abstract
Background. We have previously demonstrated that overexpression of the human MHC class Ib molecule - HLA-E/β2 microglobulin (β2m) - by tumor cells in colorectal carcinomas (CRC) was associated with an unfavorable prognosis, suggesting its involvement in tumor immune escape. However, the type of specific receptor of HLA-E/β2m expressed by tumor-infiltrating lymphocytes (TILs) - i.e inhibitory CD94/NKG2A or activating CD94/NKG2C - remains unknown yet in CRC.
Aims. We retrospectively investigated in the primary tumor of 245 CRC patients 1) the association of HLA-E/β2m overexpression and the density of CD94+ intraepithelial TILs (IEL-TILs) by immunohistochemistry with the microsatellite status of CRC, and 2) the prognostic influence of CD94+ IEL-TILs. We then further analyzed the cell type of CD94+ TIL and the type of receptor expressed - CD94/NKG2A or CD94/NKG2C - by FACS analysis from 19 freshly resected CRC tumors prospectively included.
Results. HLA-E/β2m was preferentially overexpressed in microsatellite unstable (MSI) CRC compared with microsatellite stable (MSS) CRC (44,6 % vs 18,4 % respectively, p=0.0001), and was significantly associated with a high density of CD94+ IEL-TIL in MSI (0,9% in HLA-E/β2m+ vs 0,2% in HLA-E/β2m- CRC, p=0,001), but also in MSS CRC (0,38% in HLA-E/β2m+ vs 0,15% in HLA-E/β2m- CRC, p&lt;0,0001). These CD94+ TILs mostly corresponded to αβ (50% among CD94+ cells) and CD8+ (80%) T cells, but 25% corresponded to NK cells. Both CD94+ T and NK cells preferentially expressed the inhibitory NKG2A chain, irrespective of the microsatellite status. Finally, a high density of CD94+ IEL-TILs was independently associated with a worse overall survival (p=0.03).
Conclusion. These results strongly suggest that tumor cells/immune cells interactions mediated by HLA-E/β2m and CD94/NKG2A, preferentially upregulated in MSI CRC but also found in a subset of MSS CRC, could represent a promising new druggable inhibitory immune checkpoint targeted by the anti-NKG2A monoclonal antibody (monalizumab).
Citation Format: Juliette EUGENE, Nicolas JOUAND, Delphine DANSETTE, Guillaume MEURETTE, Juliette Podevin, Tamara MATYSIAK, Stephane BEZIEAU, Christelle VOLTEAU, Wassila EL ALAMI THOMAS, Jerome CHETRITT, Olivier KERDRAON, Pierre Fourquier, Emilie THIBAUDEAU, Frederic DUMONT, Jean-Francois MOSNIER, Claire TOQUET, Anne JARRY, Nadine GERVOIS, Celine Bossard. CD94/NKG2A+ tumor-infiltrating lymphocytes in a context of HLA-E overexpression could be a promising new druggable inhibitory immune checkpoint in colorectal adenocarcinomas [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr LB-142.