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Oncoimmunology. 2018 Jan 29;7(5):e1423184. doi: 10.1080/2162402X.2017.1423184. eCollection 2018.

Expression of LLT1 and its receptor CD161 in lung cancer is associated with better clinical outcome.

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Université Côte d'Azur, CNRS UMR7275, Institut de Pharmacologie Moléculaire et Cellulaire (IPMC), Valbonne, France.
Laboratory "Immune Microenvironment and Tumors", Department "Cancer, Immunology, Immunotherapy", INSERM UMRS 1138, Cordeliers Research Center, Paris, France.
University Pierre and Marie Curie/Paris VI, Paris, France.
University Paris Descartes/Paris V, Sorbonne Paris Cité, Paris, France.
Department of Pathology, Hôpitaux Universitaires Paris Centre, AP-HP, Paris, France.
Department of Thoracic Surgery, Hôpitaux Universitaires Paris Centre, AP-HP, Paris, France.
Department of Pathology, Institut Mutualiste Montsouris, Paris, France.
University of Lyon, University Lyon 1, Lyon, France.
Institut du Thorax Curie-Montsouris, Institut Curie, Paris, France.
Thoracic Department, Institut du Thorax Curie-Montsouris, Institut Mutualiste Montsouris, Paris, France.
Paris 13 University, Sorbonne Paris Cité, Faculty of Medicine SMBH, Bobigny, France.


Co-stimulatory and inhibitory receptors expressed by immune cells in the tumor microenvironment modulate the immune response and cancer progression. Their expression and regulation are still not fully characterized and a better understanding of these mechanisms is needed to improve current immunotherapies. Our previous work has identified a novel ligand/receptor pair, LLT1/CD161, that modulates immune responses. Here, we extensively characterize its expression in non-small cell lung cancer (NSCLC). We show that LLT1 expression is restricted to germinal center (GC) B cells within tertiary lymphoid structures (TLS), representing a new hallmark of the presence of active TLS in the tumor microenvironment. CD161-expressing immune cells are found at the vicinity of these structures, with a global enrichment of NSCLC tumors in CD161+ CD4+ and CD8+ T cells as compared to normal distant lung and peripheral blood. CD161+ CD4+ T cells are more activated and produce Th1-cytokines at a higher frequency than their matched CD161-negative counterparts. Interestingly, CD161+ CD4+ T cells highly express OX40 co-stimulatory receptor, less frequently 4-1BB, and display an activated but not completely exhausted PD-1-positive Tim-3-negative phenotype. Finally, a meta-analysis revealed a positive association of CLEC2D (coding for LLT1) and KLRB1 (coding for CD161) gene expression with favorable outcome in NSCLC, independently of the size of T and B cell infiltrates. These data are consistent with a positive impact of LLT1/CD161 on NSCLC patient survival, and make CD161-expressing CD4+ T cells ideal candidates for efficient anti-tumor recall responses.


CD161; LLT1; co-stimulatory receptor; germinal center; immune checkpoints; non-small cell lung cancer; tertiary lymphoid structures; th1 response; tumor-infiltrating lymphocytes;

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