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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.

Author information

1
Université Côte d'Azur, CNRS UMR7275, Institut de Pharmacologie Moléculaire et Cellulaire (IPMC), Valbonne, France.
2
Laboratory "Immune Microenvironment and Tumors", Department "Cancer, Immunology, Immunotherapy", INSERM UMRS 1138, Cordeliers Research Center, Paris, France.
3
University Pierre and Marie Curie/Paris VI, Paris, France.
4
University Paris Descartes/Paris V, Sorbonne Paris Cité, Paris, France.
5
Department of Pathology, Hôpitaux Universitaires Paris Centre, AP-HP, Paris, France.
6
Department of Thoracic Surgery, Hôpitaux Universitaires Paris Centre, AP-HP, Paris, France.
7
Department of Pathology, Institut Mutualiste Montsouris, Paris, France.
8
University of Lyon, University Lyon 1, Lyon, France.
9
Institut du Thorax Curie-Montsouris, Institut Curie, Paris, France.
10
Thoracic Department, Institut du Thorax Curie-Montsouris, Institut Mutualiste Montsouris, Paris, France.
11
Paris 13 University, Sorbonne Paris Cité, Faculty of Medicine SMBH, Bobigny, France.

Abstract

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.

KEYWORDS:

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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