title: A high density of tertiary lymphoid structure B cells in lung tumors is associated with increased CD4+T cell receptor repertoire clonality.
abstract: T and B cell receptor (TCR and BCR, respectively) Vβ or immunoglobulin heavy chain complementarity-determining region 3 sequencing allows monitoring of repertoire changes through recognition, clonal expansion, affinity maturation, and T or B cell activation in response to antigen. TCR and BCR repertoire analysis can advance understanding of antitumor immune responses in the tumor microenvironment. TCR and BCR repertoires of sorted CD4+, CD8+or CD19+cells in tumor, non-tumoral distant tissue (NT), and peripheral compartments (blood/draining lymph node [P]) from 47 non-small cell lung cancer (NSCLC) patients (agemedian= 68 y) were sequenced. The clonotype spectra were assessed among different tissues and correlated with clinical and immunological parameters. In all tissues, CD4+and CD8+TCR repertoires had greater clonality relative to CD19+BCR. CD4+T cells exhibited greater clonality in NT compared to tumor (p= 0.002) and P (p< 0.001), concentrated among older patients (age > 68). Younger patients exhibited greater CD4+T cell diversity in P compared to older patients (p= 0.05), and greater CD4+T cell clonality in tumor relative to P (p< 0.001), with fewer shared clonotypes between tumor and P than older patients (p= 0.04). More interestingly, greater CD4+and CD8+T cell clonality in tumor and P, respectively (bothp= 0.05), correlated with high density of tumor-associated tertiary lymphoid structure (TLS) B cells, a biomarker of higher overall survival in NSCLC. Results indicate distinct adaptive immune responses in NSCLC, where peripheral T cell diversity is modulated by age, and tumor T cell clonal expansion is favored by the presence of TLSs in the tumor microenvironment.
authors.affiliation: Translational Sciences; MedImmune ; Gaithersburg, MD USA.
authors.forename: Wei
authors.initials: W
authors.lastname: Zhu
authors.affiliation: Laboratory "Cancer, Immune Control, and Escape"; INSERM UMRS 1138; Cordeliers Research Center ; Paris, France ; University Sorbonne; University Pierre and Marie Curie; UMRS 1138 ; Paris, France ; University Sorbonne Paris Cité; University Paris Descartes; UMRS 1138 ; Paris, France.
authors.forename: Claire
authors.initials: C
authors.lastname: Germain
authors.affiliation: Translational Sciences; MedImmune ; Gaithersburg, MD USA.
authors.forename: Zheng
authors.initials: Z
authors.lastname: Liu
authors.affiliation: Translational Sciences; MedImmune ; Gaithersburg, MD USA.
authors.forename: Yinong
authors.initials: Y
authors.lastname: Sebastian
authors.affiliation: Laboratory "Cancer, Immune Control, and Escape"; INSERM UMRS 1138; Cordeliers Research Center ; Paris, France ; University Sorbonne; University Pierre and Marie Curie; UMRS 1138 ; Paris, France ; University Sorbonne Paris Cité; University Paris Descartes; UMRS 1138 ; Paris, France.
authors.forename: Priyanka
authors.initials: P
authors.lastname: Devi
authors.affiliation: Laboratory "Cancer, Immune Control, and Escape"; INSERM UMRS 1138; Cordeliers Research Center ; Paris, France ; University Sorbonne; University Pierre and Marie Curie; UMRS 1138 ; Paris, France ; University Sorbonne Paris Cité; University Paris Descartes; UMRS 1138 ; Paris, France.
authors.forename: Samantha
authors.initials: S
authors.lastname: Knockaert
authors.affiliation: Translational Sciences; MedImmune ; Gaithersburg, MD USA.
authors.forename: Philip
authors.initials: P
authors.lastname: Brohawn
authors.affiliation: Translational Sciences; MedImmune ; Gaithersburg, MD USA.
authors.forename: Kim
authors.initials: K
authors.lastname: Lehmann
authors.affiliation: Laboratory "Cancer, Immune Control, and Escape"; INSERM UMRS 1138; Cordeliers Research Center ; Paris, France ; University Sorbonne; University Pierre and Marie Curie; UMRS 1138 ; Paris, France ; University Sorbonne Paris Cité; University Paris Descartes; UMRS 1138 ; Paris, France ; Department of Pathology; Cochin Hospital; AP-HP ; Paris, France.
authors.forename: Diane
authors.initials: D
authors.lastname: Damotte
authors.affiliation: Laboratory "Cancer, Immune Control, and Escape"; INSERM UMRS 1138; Cordeliers Research Center ; Paris, France ; University Sorbonne; University Pierre and Marie Curie; UMRS 1138 ; Paris, France ; University Sorbonne Paris Cité; University Paris Descartes; UMRS 1138 ; Paris, France ; Department of Pathology; Institut Mutualiste Montsouris ; Paris, France.
authors.forename: Pierre
authors.initials: P
authors.lastname: Validire
authors.affiliation: Translational Sciences; MedImmune ; Gaithersburg, MD USA.
authors.forename: Yihong
authors.initials: Y
authors.lastname: Yao
authors.affiliation: Oncology Research; MedImmune ; Cambridge, UK.
authors.forename: Viia
authors.initials: V
authors.lastname: Valge-Archer
authors.affiliation: Oncology Research; MedImmune ; Gaithersburg, MD USA.
authors.forename: Scott A
authors.initials: SA
authors.lastname: Hammond
authors.affiliation: Laboratory "Cancer, Immune Control, and Escape"; INSERM UMRS 1138; Cordeliers Research Center ; Paris, France ; University Sorbonne; University Pierre and Marie Curie; UMRS 1138 ; Paris, France ; University Sorbonne Paris Cité; University Paris Descartes; UMRS 1138 ; Paris, France.
authors.forename: Marie-Caroline
authors.initials: MC
authors.lastname: Dieu-Nosjean
authors.affiliation: Translational Sciences; MedImmune ; Gaithersburg, MD USA.
authors.forename: Brandon W
authors.initials: BW
authors.lastname: Higgs
keywords: TCR/BCR repertoire; deep sequencing; non-small cell lung cancer; tertiary lymphoid structure