title: Dendritic cells in tumor-associated tertiary lymphoid structures signal a Th1 cytotoxic immune contexture and license the positive prognostic value of infiltrating CD8+ T cells.
abstract: Tumor-infiltrating T cells, particularly CD45RO(+)CD8(+) memory T cells, confer a positive prognostic value in human cancers. However, the mechanisms that promote a protective T-cell response in the tumor microenvironment remain unclear. In chronic inflammatory settings such as the tumor microenvironment, lymphoid neogenesis can occur to create local lymph node-like structures known as tertiary lymphoid structures (TLS). These structures can exacerbate a local immune response, such that TLS formation in tumors may help promote an efficacious immune contexture. However, the role of TLS in tumors has yet to be investigated carefully. In lung tumors, mature dendritic cells (DC) present in tumor-associated TLS can provide a specific marker of these structures. In this study, we evaluated the influence of TLS on the characteristics of the immune infiltrate in cohorts of prospective and retrospective human primary lung tumors (n = 458). We found that a high density of mature DC correlated closely to a strong infiltration of T cells that are predominantly of the effector-memory phenotype. Moreover, mature DC density correlated with expression of genes related to T-cell activation, T-helper 1 (Th1) phenotype, and cytotoxic orientation. Lastly, a high density of TLS-associated DC correlated with long-term survival, which also allowed a distinction of patients with high CD8(+) T-cell infiltration but a high risk of death. Taken together, our results show how tumors infiltrated by TLS-associated mature DC generate a specific immune contexture characterized by a strong Th1 and cytotoxic orientation that confers the lowest risk of death. Furthermore, our findings highlight the pivotal function of TLS in shaping the immune character of the tumor microenvironment, in promoting a protective immune response mediated by T cells against cancer.
authors.affiliation: Authors' Affiliations: Laboratory Immune Microenvironment and Tumors, INSERM U872, Cordeliers Research Center; University Pierre et Marie Curie; University Paris Descartes, UMRS 872; Departments of Pathology and Thoracic Surgery, Hôtel Dieu Hospital, AP-HP; Department of Pathology, Institut Mutualiste Montsouris; Department of Immunology, European Georges Pompidou Hospital, AP-HP, Paris, France; and Oncology Research, MedImmune LLC, Gaithersburg, Maryland.
authors.forename: Jérémy
authors.initials: J
authors.lastname: Goc
authors.forename: Claire
authors.initials: C
authors.lastname: Germain
authors.forename: Thi Kim Duy
authors.initials: TK
authors.lastname: Vo-Bourgais
authors.forename: Audrey
authors.initials: A
authors.lastname: Lupo
authors.forename: Christophe
authors.initials: C
authors.lastname: Klein
authors.forename: Samantha
authors.initials: S
authors.lastname: Knockaert
authors.forename: Luc
authors.initials: L
authors.lastname: de Chaisemartin
authors.forename: Hanane
authors.initials: H
authors.lastname: Ouakrim
authors.forename: Etienne
authors.initials: E
authors.lastname: Becht
authors.forename: Marco
authors.initials: M
authors.lastname: Alifano
authors.forename: Pierre
authors.initials: P
authors.lastname: Validire
authors.forename: Romain
authors.initials: R
authors.lastname: Remark
authors.forename: Scott A
authors.initials: SA
authors.lastname: Hammond
authors.forename: Isabelle
authors.initials: I
authors.lastname: Cremer
authors.forename: Diane
authors.initials: D
authors.lastname: Damotte
authors.forename: Wolf-Herman
authors.initials: WH
authors.lastname: Fridman
authors.forename: Catherine
authors.initials: C
authors.lastname: Sautès-Fridman
authors.forename: Marie-Caroline
authors.initials: MC
authors.lastname: Dieu-Nosjean
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology / Q000378:metabolism; D002454:Cell Differentiation / Q000276:immunology; D016000:Cluster Analysis; D003602:Cytotoxicity, Immunologic; D003713:Dendritic Cells / Q000166:cytology / Q000276:immunology*; D005260:Female; D020869:Gene Expression Profiling; D006801:Humans; D007156:Immunologic Memory; D008175:Lung Neoplasms / Q000235:genetics / Q000276:immunology* / Q000401:mortality / Q000473:pathology*; D008213:Lymphocyte Activation / Q000276:immunology; D016246:Lymphocytes, Tumor-Infiltrating / Q000276:immunology* / Q000378:metabolism; D008297:Male; D008875:Middle Aged; D009367:Neoplasm Staging; D011379:Prognosis; D012307:Risk Factors; D016176:T-Lymphocyte Subsets / Q000276:immunology* / Q000378:metabolism; D018417:Th1 Cells; D059016:Tumor Microenvironment / Q000276:immunology; D055815:Young Adult