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Long-Term Survival for Patients With Non–Small-Cell Lung Cancer With Intratumoral Lymphoid Structures

Marie-Caroline Dieu-Nosjean, Martine Antoine, Claire Danel, Didier Heudes, Marie Wislez, Virginie Poulot, Nathalie Rabbe, Ludivine Laurans, Eric Tartour, Luc de Chaisemartin, Serge Lebecque, Wolf-Herman Fridman, Jacques Cadranel

From the Laboratoire Microenvironnement Immunitaire et Tumeurs, Institut National de la Santé et de la Recherche Médicale (INSERM) U872, Centre de Recherche des Cordeliers; Université Pierre et Marie Curie, UMR S872; Université Paris Descartes, UMR S872; Service d'Anatomie-Pathologie, Hôpital Tenon, AP-HP; Laboratoire de Biologie Cellulaire et d'Immunopathologie Pulmonaire, UPRES EA3493, Université Paris VI, Hôpital Tenon; Service d'Anatomie-Pathologie, Hôpital Européen Georges Pompidou, AP-HP; Service de Pneumologie et Réanimation Respiratoire, Hôpital Tenon, AP-HP; Laboratoire d'Immunologie, Hôpital Européen Georges Pompidou, AP-HP, Paris; INSERM U503, CERVI; and Centre Hospitalier Lyon Sud, Lyon, France

Corresponding author: Marie-Caroline Dieu-Nosjean, PhD, Laboratoire Microenvironnement Immunitaire et Tumeurs, INSERM UMR S872, Centre de Recherche des Cordeliers, 15 rue de l'école de Médecine, F-75270 Paris cedex 06, France; e-mail: mc.dieu-nosjean{at}crc.jussieu.fr

Purpose It has been established that the immune system plays an important role in tumor rejection. There is also compelling evidence that immune responses can develop independently of secondary lymphoid organs in tertiary lymphoid structures. We studied the presence and the correlation of tertiary lymphoid structures with clinical outcome in non–small-cell lung cancer (NSCLC), as the prognostic value of these structures in patients with cancer had not yet been established.

Patients and Methods This retrospective study was performed by immunohistochemistry on paraffin-embedded tissue specimens from 74 patients with early-stage NSCLC.

Results Tertiary lymphoid structures were detected in some tumors but not in nontumoral lungs. Thus we called these structures tumor-induced bronchus-associated lymphoid tissue (Ti-BALT). As in lymph nodes, Ti-BALTs were composed of mature dendritic cell (DC)/T-cell clusters adjacent to B-cell follicles and had features of an ongoing immune response. Because the quantitative counting of Ti-BALT was difficult to achieve, we used mature DCs that homed exclusively in Ti-BALT as a specific marker of these structures. Univariate analysis showed that the density of mature DCs was highly associated with a favorable clinical outcome (overall, disease-specific, and disease-free survival), suggesting that Ti-BALT may participate in antitumoral immunity. The density of tumor-infiltrating lymphocytes, in particular, CD4⁺ and T-bet⁺ Th1 T cells, was profoundly decreased in tumors weakly infiltrated by mature DCs.

Conclusion The density of mature DCs was found to be a better predictor of clinical outcome than the other parameters tested. The number of tumor-infiltrating mature DCs may identify patients with early-stage NSCLC who have a high risk of relapse.

Supported by Grant No. ARC n°C01-010 from Association pour la Recherche sur le Cancer through the Alliance pour la Recherche sur le Cancer network.

M.A. and C.D. contributed equally to this study.

Authors’ disclosures of potential conflicts of interest and author contributions are found at the end of this article.

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